{"gene":"PF3D7_1335900","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":1997,"finding":"TRAP is essential for sporozoite gliding motility in vitro and for infection of mosquito salivary glands and the vertebrate liver, as demonstrated by gene disruption (knockout) in Plasmodium berghei, which abolished gliding motility and infectivity while leaving erythrocytic cycle and oocyst development intact.","method":"Gene targeting / homologous recombination knockout in P. berghei; in vitro gliding motility assay; sporozoite infectivity assays in mosquitoes and rodents","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with specific phenotypic readouts (gliding motility, salivary gland invasion, liver infectivity), replicated across multiple downstream studies","pmids":["9267031"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":1988,"finding":"TRAP (PF3D7_1335900) was cloned and sequenced from P. falciparum; it encodes a protein containing the WSPCSVTCG thrombospondin motif (also found in circumsporozoite proteins and properdin) and an RGD cell-recognition motif, and is expressed during the erythrocytic stage.","method":"Gene cloning, DNA sequencing, sequence homology analysis","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original cloning and sequence characterization, single lab, no in vitro functional assay beyond sequence inference","pmids":["3045563"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1993,"finding":"Recombinant TRAP constructs expressed in E. coli bind specifically to sulfated glycoconjugates (sulfatides) and to the surface of HepG2 hepatoma cells; these interactions depend on the conserved WSPCSVTCG motif and are inhibited by sulfated glycoconjugates and suramin. Antisera against TRAP constructs inhibit sporozoite invasion of HepG2 cells.","method":"Recombinant protein binding assays (sulfatide binding, HepG2 cell binding); inhibition assays with sulfated glycoconjugates and suramin; neutralization assays with antisera","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution with recombinant protein, motif-dependence established, functional invasion inhibition shown; single lab but multiple orthogonal methods","pmids":["8392935"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1995,"finding":"Recombinant TRAP binds to the basolateral cell membrane of human hepatocytes in the Disse's space, with sulfated glycoconjugates functioning as TRAP ligands on hepatocytes. TRAP expression in P. falciparum sporozoites is absent in oocysts, variable in hemocoel sporozoites, and uniform in salivary gland sporozoites, indicating developmentally regulated expression linked to infectivity.","method":"Recombinant TRAP binding assays on hepatocytes; immunofluorescence and localization studies during sporozoite development in mosquito stages","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay and localization with functional correlation to infectivity stage; single lab, two methods","pmids":["7664729"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"finding":"TRAP (PfSSP2) localizes to sporozoite micronemes by immunoelectron microscopy and to the surface membrane by live immunofluorescence; antibodies against recombinant TRAP inhibit sporozoite invasion and development in hepatocytes in vitro.","method":"Immunoelectron microscopy; live immunofluorescence; in vitro sporozoite invasion inhibition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to micronemes by EM plus functional inhibition; single lab, two orthogonal methods","pmids":["1409621"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1999,"finding":"The A-domain and TSR motif of P. falciparum TRAP are both required for mosquito salivary gland invasion. Transgenic P. berghei expressing PfTRAP with a point mutation in the conserved A-domain residue or a deletion in the TSP motif showed impaired salivary gland invasion; midgut sporozoites with A-domain mutation retained motility while TSP motif deletion abolished gliding motility. Both mutants remained able to infect mice from the midgut stage.","method":"Gene replacement in P. berghei with site-directed mutant PfTRAP constructs; gliding motility assay; salivary gland invasion assay; mouse infectivity assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — transgenic replacement with specific domain mutants, multiple functional readouts (motility, salivary gland invasion, mouse infectivity), clearly separating roles of each domain","pmids":["10508153"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2002,"finding":"Loss-of-function mutations in the integrin-like A-domain and the thrombospondin type I repeat (TSR) of TRAP's ectodomain specifically decrease sporozoite invasion of host cells (mosquito salivary glands and vertebrate cells) without affecting gliding motility or cell adhesion; mutations in both modules render sporozoites non-invasive in all host cell types tested. The two adhesive modules act as independently active binding domains interacting with distinct cell receptors.","method":"Site-directed mutagenesis of TRAP ectodomain modules in P. berghei; sporozoite invasion assays in multiple cell types (mosquito salivary glands, CHO cells, human/hamster hepatoma cells); gliding motility assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-function mutagenesis with multiple host cell types and orthogonal phenotypic readouts, cleanly separating adhesion from invasion","pmids":["11927544"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2003,"finding":"Aldolase specifically interacts with the C-terminal cytoplasmic domain of TRAP family adhesins, including TRAP; this interaction is disrupted by mutation of a critical tryptophan in the C-terminal domain previously shown to be essential for parasite motility, identifying aldolase as a bridge between TRAP and the actin cytoskeleton.","method":"Co-immunoprecipitation; pulldown assays; site-directed mutagenesis of the C-terminal tryptophan residue","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding reconstitution with mutagenesis validating critical residue; finding independently supported by structural work (PMID 17426153)","pmids":["12718875"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"The cytoplasmic tail of TRAP binds the actin-bridging protein aldolase in vitro, linking the extracellular adhesin to the actin-myosin motor complex. Homologues of glideosome-associated proteins (GAP40, GAP50) and a merozoite TRAP homologue (MTRAP) sharing TRAP's key features (thrombospondin repeat, rhomboid-protease cleavage site, aldolase-binding cytoplasmic tail) are present in P. falciparum merozoites.","method":"In vitro aldolase binding assay with TRAP cytoplasmic tail; comparative genomic and protein domain analysis; localization studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay for TRAP cytoplasmic tail-aldolase interaction; single lab","pmids":["16321976"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"P. falciparum rhomboid protease PfROM4 cleaves TRAP in a heterologous assay, dependent on the TRAP transmembrane domain; PfROM1 also shows activity toward TRAP. This identifies rhomboid proteases as the enzymes responsible for TRAP shedding during sporozoite invasion.","method":"Heterologous rhomboid cleavage assay; transmembrane domain swap experiments establishing substrate specificity","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — enzymatic assay in heterologous system with domain-swap controls; first enzymatic characterization of PfROMs on TRAP; single lab","pmids":["17040128"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"The NMR solution structure of the TSR domain of P. falciparum TRAP reveals an elongated structure stabilized by a tryptophan-arginine ladder and disulfide bonds; heparin binding maps to the N-terminal half of the TSR domain with a tetrasaccharide as the minimal binding fragment.","method":"Solution NMR structure determination; chemical shift mapping of heparin binding epitope; heparin fragment binding assays","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation of heparin binding site; single lab but rigorous structural method","pmids":["16815922"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"Crystal structures of P. falciparum aldolase (PfAldo) at 2.4 Å and 2.7 Å resolution with the C-terminal hexapeptide of TRAP (from P. berghei) show that the penultimate tryptophan of TRAP fits into a newly formed induced-fit hydrophobic pocket on aldolase delimited by hydrophilic residues (two arginines, one glutamate, one glutamine). Mutagenesis of PfAldo residues in and near this induced pocket reduces TRAP binding; the TRAP- and actin-binding sites on aldolase overlap.","method":"X-ray crystallography (2.4 Å and 2.7 Å); site-directed mutagenesis of aldolase residues; structural comparison with unliganded PfAldo","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus mutagenesis validation; mechanistic insight into how TRAP tail engages aldolase","pmids":["17426153"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"TRAP interacts with the Anopheles salivary gland protein saglin; point mutations in TRAP's A-domain binding domain abolish saglin binding, and the SM1 peptide (a mimotope of TRAP) competes for binding. In vivo knockdown of saglin strongly inhibits salivary gland invasion by Plasmodium sporozoites.","method":"UV-crosslinking of SM1 peptide to salivary gland target; anti-SM1 antibody identification of TRAP as mimotope; binding competition assays; point mutation analysis of TRAP A-domain; in vivo saglin RNAi knockdown","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (crosslinking, competition, mutagenesis, in vivo RNAi), identifying both the parasite ligand domain and the mosquito receptor","pmids":["19148273"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Crystal structures of TRAP VWA and TSR domains from P. vivax and P. falciparum reveal that the VWA domain adopts closed and open conformations with Mg2+ binding at a MIDAS; in the open conformation, an extensible β-ribbon (disulfide-bonded segments flanking the VWA domain) is extended 15 Å and the TSR domain becomes ordered. The open conformation is stabilized by tensile force from the actin motility apparatus, providing a structural mechanism for 'stick-and-slip' motility regulation.","method":"X-ray crystallography (multiple crystal forms); structural comparison of closed vs. open states; identification of MIDAS metal coordination","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures in multiple lattices from two species establishing conformational switching mechanism with functional interpretation","pmids":["23236185"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Shedding of TRAP by a rhomboid protease is essential for sporozoite gliding motility and infectivity. Mutations introduced into the TRAP rhomboid-cleavage site within the transmembrane domain resulted in defective TRAP shedding, slow staccato motility, and reduced infectivity. Mutation of both the rhomboid-cleavage site and an alternate cleavage site produced non-motile, non-infectious sporozoites, demonstrating that TRAP removal from the sporozoite surface by proteolytic shedding is required to break adhesive contacts and enable continuous forward movement.","method":"Site-directed mutagenesis of rhomboid cleavage site and alternate cleavage site in TRAP transmembrane domain in P. berghei; TRAP shedding assay; gliding motility assay; infectivity assays (intradermal and intravenous inoculation)","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of cleavage sites with multiple functional readouts (shedding, motility, infectivity by two routes); mechanistically causal","pmids":["22911675"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2001,"finding":"Gene disruption of TRAP in P. yoelii phenocopies P. berghei TRAP knockout: TRAP-null sporozoites fail to glide and cannot invade mosquito salivary glands, while erythrocytic cycle, gametocyte, and oocyst development are unaffected. Sporozoite morphology appears normal.","method":"Gene targeting by site-specific integration in P. yoelii; gliding motility assay; salivary gland invasion assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific phenotypic readouts; replicates P. berghei finding in a second rodent malaria species","pmids":["11295181"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2003,"finding":"The cytoplasmic domain of TRAP can functionally substitute for the cytoplasmic domain of EBA-175 in P. falciparum merozoite invasion of erythrocytes, demonstrating that the TRAP cytoplasmic domain encodes a conserved signal recognized by the parasite's invasion machinery regardless of the invasive stage.","method":"Cytoplasmic domain swap (chimeric EBA-175 with TRAP cytoplasmic tail) in P. falciparum; erythrocyte invasion assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic domain-swap with functional invasion readout; single lab","pmids":["12876279"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2000,"finding":"Antibodies against TRAP (A-domain, conserved N-terminus, and repeat region) have no effect on sporozoite gliding motility or infectivity to mice in vivo. TRAP is normally located in micronemes and is present at very low levels on the sporozoite surface; calcium ionophore treatment or contact with hepatoma cells induces dramatic relocalization of TRAP to the parasite surface.","method":"In vivo mouse sporozoite challenge after immunization; monoclonal and polyclonal antibody gliding inhibition assays; immunofluorescence localization; calcium ionophore treatment","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result for antibody inhibition in vivo plus direct localization showing stimulus-induced surface exposure; multiple methods, single lab","pmids":["10816526"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2002,"finding":"Recombinant P. falciparum TRAP binds to heparan sulphate proteoglycans on hepatocytes and both heparan and chondroitin sulphate proteoglycans on stellate cells; TRAP binding to Kupffer cells is glycosaminoglycan-independent.","method":"Recombinant TRAP binding assays on primary liver cells (Kupffer cells, hepatocytes, stellate cells, sinusoidal endothelia); competitive inhibition with specific glycosaminoglycans","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with recombinant protein on primary cells, cell-type-specific receptor specificity established; single lab","pmids":["12139612"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"Mass spectrometry of chemically labeled P. falciparum salivary gland sporozoites provides the first direct evidence that TRAP is glycosylated on the sporozoite surface; TRAP was surface-exposed and accessible to antibodies on live sporozoites.","method":"Chemical surface labeling of live sporozoites; mass spectrometry-based proteomics; antibody accessibility assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct MS evidence of glycosylation on native protein; single lab, two complementary methods","pmids":["27128092"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"POFUT2 (Plasmodium protein O-fucosyltransferase 2) is responsible for O-fucosylation of TRAP. Genetic disruption of POFUT2 in P. falciparum results in destabilization and incorrect trafficking of TRAP (and other TSR-bearing proteins), impairing gliding motility, cell traversal, hepatocyte invasion, and production of exoerythrocytic forms.","method":"Genetic disruption of POFUT2; assessment of TRAP stability and trafficking; gliding motility assay; cell traversal assay; hepatocyte invasion assay; humanized chimeric liver mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO identifying the writer enzyme, multiple downstream functional phenotypes established, mechanism (quality-control-dependent trafficking) proposed and supported","pmids":["28916755"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"A putative pantothenate transporter PAT is a membrane component of sporozoite micronemes and is required for secretion of TRAP-containing vesicles to the sporozoite surface; PAT-deficient P. berghei sporozoites fail to secrete TRAP, are immotile, and unable to infect the rodent host.","method":"Gene disruption of PAT in P. berghei; TRAP secretion assay; gliding motility assay; rodent infectivity assay; localization by immunofluorescence","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with TRAP secretion and motility phenotypes, mechanistically linking PAT to TRAP exocytosis; single lab","pmids":["27427910"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2010,"finding":"TRAP (together with S6) is important for initial adhesion of sporozoites to flat surfaces; total internal reflection fluorescence microscopy and flow experiments reveal that sporozoite adhesion is a multistep, developmentally regulated process in which TRAP participates in the earliest adhesion step.","method":"Total internal reflection fluorescence (TIRF) microscopy; sporozoite flow assays; genetic analysis of TRAP and S6 surface proteins","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging-based localization and adhesion assay linking TRAP to initial adhesion step; single lab","pmids":["20159960"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"O-fucosylation (at Thr256) and C-mannosylation (at Trp250) of the TSR domain of P. falciparum TRAP are both individually required for TRAP protein stability and function: CRISPR/Cas9-generated glyco-null mutants (T256A and W250F) show significantly reduced TRAP protein abundance despite normal transcript levels, are unable to colonize mosquito salivary glands, and are severely impaired in gliding motility and hepatocyte invasion in vitro.","method":"CRISPR/Cas9 site-directed mutagenesis of glycosylation sites in P. falciparum TRAP; western blot quantification of TRAP protein abundance; gliding motility assay; salivary gland colonization assay; hepatocyte invasion assay; comparison with TRAP knockout line","journal":"bioRxiv : the preprint server for biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous site-specific mutagenesis at two glycosylation residues with multiple functional readouts and protein-level quantification; preprint but mechanistically comprehensive","pmids":["40667256"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":1997,"finding":"Transgenic P. berghei sporozoites with TRAP disrupted by gene targeting fail to glide and fail to invade mosquito salivary glands but develop normally through erythrocytic, gametocyte, and oocyst stages, directly confirming TRAP's essential role in sporozoite-stage motility.","method":"Gene targeting by homologous recombination in P. berghei; gliding motility assay; salivary gland invasion assay; blood stage and mosquito stage phenotyping","journal":"Lancet (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific motility and invasion phenotypes, consistent with PMID 9267031; reported as short communication","pmids":["9251640"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"TRAP (PF3D7_1335900) is a type I transmembrane micronemal protein of Plasmodium sporozoites whose extracellular A-domain (von Willebrand factor-like, adopting open/closed conformations) and TSR domain bind host-cell receptors—including heparan sulfate proteoglycans on hepatocytes and the Anopheles salivary gland protein saglin—while its cytoplasmic tail is linked to the parasite actin-myosin motor via aldolase; after being translocated rearward by the motor to power gliding motility, TRAP is shed by rhomboid proteases (principally PfROM4) to break adhesive contacts and allow continuous forward movement, and this entire cycle depends on POFUT2-mediated O-fucosylation and C-mannosylation of the TSR domain for proper protein folding, ER quality-control trafficking, and stability."},"narrative":{"mechanistic_narrative":"TRAP (PF3D7_1335900) is a type I transmembrane micronemal adhesin of Plasmodium sporozoites that couples host-cell recognition to the parasite's actin-myosin motor and is essential for gliding motility and productive invasion of both mosquito salivary glands and the vertebrate liver [PMID:9267031, PMID:10508153]. Genetic disruption in P. berghei and P. yoelii abolishes gliding and salivary-gland invasion while leaving erythrocytic, gametocyte, and oocyst development intact, defining TRAP as a sporozoite-stage motility and invasion factor [PMID:9267031, PMID:11295181]. Its ectodomain carries two independently active adhesive modules — an integrin-like von Willebrand factor A-domain and a thrombospondin type I repeat (TSR) — that engage distinct host receptors: the TSR binds heparin/heparan sulfate proteoglycans on hepatocytes through its N-terminal half [PMID:16815922, PMID:12139612], while the A-domain binds the Anopheles salivary-gland protein saglin [PMID:19148273]. Structure-function mutagenesis separates roles cleanly: the two modules mediate host-cell invasion via distinct receptors, whereas the TSR is additionally required for gliding motility itself [PMID:10508153, PMID:11927544]. The A-domain switches between closed and open conformations coordinated by a MIDAS Mg2+ site, and force from the motor stabilizes the open state via an extensible β-ribbon, providing a structural basis for stick-and-slip motility [PMID:23236185]. On the cytoplasmic side, the C-terminal tail—via a critical penultimate tryptophan that inserts into an induced-fit pocket on aldolase overlapping its actin-binding site—bridges TRAP to the actin cytoskeleton, and this tail encodes a conserved invasion signal transferable to other invasins [PMID:12718875, PMID:17426153, PMID:12876279]. Productive motility requires proteolytic shedding of TRAP by rhomboid proteases (PfROM4, with PfROM1 activity) at a transmembrane cleavage site, which breaks rearward adhesive contacts to enable continuous forward movement [PMID:17040128, PMID:22911675]. The entire cycle depends on TSR glycosylation: O-fucosylation by POFUT2 and site-specific O-fucosylation (Thr256) and C-mannosylation (Trp250) are each required for TRAP folding, stability, and correct trafficking, and secretion of TRAP-containing micronemal vesicles requires the transporter PAT [PMID:28916755, PMID:27427910, PMID:40667256].","teleology":[{"year":1988,"claim":"Before any functional data, the question was what TRAP is; molecular cloning revealed a protein carrying a thrombospondin (WSPCSVTCG) motif and an RGD adhesion motif, hinting at an adhesive function.","evidence":"Gene cloning and sequencing of P. falciparum TRAP with sequence-homology analysis","pmids":["3045563"],"confidence":"Medium","gaps":["No functional assay beyond sequence inference","Stage assignment reported as erythrocytic, later refined to sporozoite stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"claim":"To place TRAP subcellularly and test relevance to infection, immuno-EM localized it to sporozoite micronemes with stimulus-dependent surface exposure, and anti-TRAP antibodies blocked hepatocyte invasion, establishing it as an invasion-relevant surface/micronemal protein.","evidence":"Immunoelectron microscopy, live immunofluorescence, and in vitro invasion inhibition in P. falciparum","pmids":["1409621"],"confidence":"Medium","gaps":["Molecular receptor not identified","Mechanism of surface relocalization unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1993,"claim":"The receptor question was first addressed by showing recombinant TRAP binds sulfated glycoconjugates and hepatoma cells in a WSPCSVTCG-motif-dependent manner, defining glycosaminoglycan-type ligands as TRAP binding partners on host cells.","evidence":"Recombinant protein binding, motif-dependence and suramin/sulfatide inhibition, antisera neutralization in P. falciparum","pmids":["8392935"],"confidence":"High","gaps":["Native protein binding not yet shown","In vivo relevance of the binding not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1997,"claim":"Whether TRAP is genuinely essential was settled by knockout in P. berghei, which abolished gliding motility, salivary-gland invasion, and liver infectivity without disrupting other life-cycle stages, defining TRAP as a dedicated sporozoite motility/invasion factor.","evidence":"Homologous-recombination knockout plus gliding and infectivity assays in P. berghei","pmids":["9267031","9251640"],"confidence":"High","gaps":["Does not distinguish adhesion from motility from invasion roles","No molecular mechanism of motor coupling"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2001,"claim":"To confirm the phenotype was not species-idiosyncratic, TRAP disruption in P. yoelii reproduced the non-gliding, non-invasive sporozoite phenotype, generalizing TRAP's essential role across rodent malaria species.","evidence":"Site-specific knockout, gliding and salivary-gland invasion assays in P. yoelii","pmids":["11295181"],"confidence":"Medium","gaps":["Does not address vertebrate-cell-type specificity","No domain-level dissection"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2002,"claim":"The functional question of what each ectodomain module does was answered by mutagenesis showing the A-domain and TSR act as independent binding modules for distinct receptors, and that loss of both blocks invasion of all host cell types without affecting motility or adhesion.","evidence":"Site-directed mutagenesis of ectodomain modules with multi-cell-type invasion and motility assays in P. berghei; plus cell-type-specific GAG-binding of recombinant TRAP on primary liver cells","pmids":["11927544","12139612"],"confidence":"High","gaps":["Identity of the A-domain host receptor not yet known","Cross-talk between modules unresolved"],"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"How the extracellular adhesin transmits force inward was addressed by identifying aldolase as the cytoplasmic-tail partner bridging TRAP to actin, dependent on a critical C-terminal tryptophan, and by showing the tail carries a transferable, conserved invasion signal.","evidence":"Co-IP, pulldown and tryptophan mutagenesis (aldolase); EBA-175/TRAP cytoplasmic domain swap in P. falciparum","pmids":["12718875","12876279"],"confidence":"High","gaps":["Direct demonstration of force transmission in vivo not shown","Full glideosome composition not defined here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"The structural basis of the TRAP-aldolase link was resolved: the penultimate tryptophan of TRAP inserts into an induced-fit pocket on aldolase that overlaps the actin-binding site, explaining how the adhesin engages the motor.","evidence":"X-ray crystallography of PfAldo with TRAP C-terminal peptide plus aldolase mutagenesis","pmids":["17426153"],"confidence":"High","gaps":["Stoichiometry within the intact glideosome unresolved","Regulation of the interaction during motility not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"The TSR structure and its receptor engagement were defined by NMR, revealing a Trp-Arg-ladder/disulfide-stabilized fold with heparin binding localized to the N-terminal half, mapping the hepatocyte-receptor contact.","evidence":"NMR solution structure and heparin-fragment binding mapping of the P. falciparum TSR domain","pmids":["16815922"],"confidence":"High","gaps":["Structure of full ectodomain not resolved here","In vivo relevance of the minimal tetrasaccharide binding not shown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"The enzymatic basis of TRAP turnover at the surface was addressed by showing rhomboid proteases PfROM4 (and PfROM1) cleave TRAP in a transmembrane-domain-dependent manner, nominating the sheddases responsible for releasing TRAP.","evidence":"Heterologous rhomboid cleavage assay with transmembrane-domain swaps","pmids":["17040128"],"confidence":"Medium","gaps":["Physiological relevance shown only in heterologous system","Relative in vivo contribution of PfROM4 vs PfROM1 not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"To pinpoint when TRAP acts during locomotion, TIRF and flow imaging placed TRAP in the earliest adhesion step of a multistep, developmentally regulated adhesion process.","evidence":"TIRF microscopy and flow adhesion assays with TRAP and S6 mutants in P. berghei","pmids":["20159960"],"confidence":"Medium","gaps":["Molecular receptor for initial adhesion not identified","Contribution relative to other adhesins not quantified"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2012,"claim":"Two complementary studies answered how motility is mechanically regulated: crystal structures revealed a MIDAS-controlled closed/open A-domain switch stabilized by tensile force via an extensible β-ribbon, and cleavage-site mutagenesis showed rhomboid shedding of TRAP is required to break adhesive contacts for continuous movement.","evidence":"X-ray crystallography of VWA/TSR domains from P. vivax and P. falciparum; cleavage-site mutagenesis with shedding, motility, and infectivity assays in P. berghei","pmids":["23236185","22911675"],"confidence":"High","gaps":["Direct measurement of force-dependent conformational switching in living parasites not achieved","In vivo identity of the sheddase not genetically confirmed here"],"attribution":[{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2009,"claim":"The mosquito-side receptor question was answered by identifying saglin as the A-domain-binding salivary-gland partner whose knockdown blocks sporozoite invasion, defining the receptor for salivary-gland tropism.","evidence":"SM1 mimotope crosslinking, competition, A-domain point mutation, and in vivo saglin RNAi in P. falciparum","pmids":["19148273"],"confidence":"High","gaps":["Affinity and structural basis of the TRAP-saglin interaction not resolved","Whether saglin is the sole salivary-gland receptor unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Native-state questions were addressed by demonstrating TRAP is glycosylated and surface-exposed on live salivary-gland sporozoites, and that secretion of TRAP-containing micronemal vesicles requires the transporter PAT.","evidence":"Surface chemical labeling and mass spectrometry on live P. falciparum sporozoites; PAT knockout with TRAP secretion and motility assays in P. berghei","pmids":["27128092","27427910"],"confidence":"Medium","gaps":["Glycan structures not mapped at this stage","Mechanism by which PAT enables microneme exocytosis unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"claim":"The enzyme responsible for TRAP TSR glycosylation and its functional importance were established: POFUT2 O-fucosylates TRAP, and its loss destabilizes and mis-traffics TRAP, impairing motility, traversal, and hepatocyte invasion, linking glycosylation to ER quality control.","evidence":"POFUT2 genetic disruption with TRAP stability/trafficking, motility, traversal, invasion assays and humanized-liver mouse model in P. falciparum","pmids":["28916755"],"confidence":"High","gaps":["Site of O-fucosylation on TRAP not pinpointed in this study","Direct structural consequence of the modification on folding unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"The specific glycosylation residues were dissected, showing O-fucosylation at Thr256 and C-mannosylation at Trp250 are each individually required for TRAP protein stability and for salivary-gland colonization, gliding, and hepatocyte invasion.","evidence":"CRISPR/Cas9 T256A and W250F mutants with protein-abundance quantification and functional assays in P. falciparum NF54 (preprint)","pmids":["40667256"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","Structural mechanism by which each glycan stabilizes the TSR fold not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":null,"claim":"How the A-domain force-driven conformational switch, TSR receptor engagement, rhomboid shedding, and aldolase-mediated motor coupling are temporally coordinated during a single traction cycle in the living sporozoite remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated 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CO-PARTICIPANT IN EARLY SPOROZOITE ADHESION [#22]"],"other_free_text":["Type I transmembrane micronemal adhesin of Plasmodium sporozoites; extracellular region contains an integrin-like von Willebrand factor A-domain and a thrombospondin type I repeat (TSR) [#1, #6, #10].","A-domain adopts closed and open conformations with Mg2+ at a MIDAS; the open state is stabilized by tensile force via an extensible β-ribbon, supporting a stick-and-slip motility mechanism [#13].","TSR fold stabilized by a tryptophan-arginine ladder and disulfide bonds; heparin binding maps to the N-terminal half with a tetrasaccharide as minimal ligand [#10].","Cytoplasmic tail carries a conserved invasion signal transferable to EBA-175, and engages aldolase through a penultimate tryptophan inserted into an induced-fit pocket overlapping aldolase's actin-binding site [#7, #11, #16].","TSR is post-translationally modified by O-fucosylation (Thr256) and C-mannosylation (Trp250), each required for TRAP stability and 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demonstrated by gene disruption (knockout) in Plasmodium berghei, which abolished gliding motility and infectivity while leaving erythrocytic cycle and oocyst development intact.\",\n      \"method\": \"Gene targeting / homologous recombination knockout in P. berghei; in vitro gliding motility assay; sporozoite infectivity assays in mosquitoes and rodents\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with specific phenotypic readouts (gliding motility, salivary gland invasion, liver infectivity), replicated across multiple downstream studies\",\n      \"pmids\": [\"9267031\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"TRAP (PF3D7_1335900) was cloned and sequenced from P. falciparum; it encodes a protein containing the WSPCSVTCG thrombospondin motif (also found in circumsporozoite proteins and properdin) and an RGD cell-recognition motif, and is expressed during the erythrocytic stage.\",\n      \"method\": \"Gene cloning, DNA sequencing, sequence homology analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original cloning and sequence characterization, single lab, no in vitro functional assay beyond sequence inference\",\n      \"pmids\": [\"3045563\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Recombinant TRAP constructs expressed in E. coli bind specifically to sulfated glycoconjugates (sulfatides) and to the surface of HepG2 hepatoma cells; these interactions depend on the conserved WSPCSVTCG motif and are inhibited by sulfated glycoconjugates and suramin. Antisera against TRAP constructs inhibit sporozoite invasion of HepG2 cells.\",\n      \"method\": \"Recombinant protein binding assays (sulfatide binding, HepG2 cell binding); inhibition assays with sulfated glycoconjugates and suramin; neutralization assays with antisera\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution with recombinant protein, motif-dependence established, functional invasion inhibition shown; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8392935\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Recombinant TRAP binds to the basolateral cell membrane of human hepatocytes in the Disse's space, with sulfated glycoconjugates functioning as TRAP ligands on hepatocytes. TRAP expression in P. falciparum sporozoites is absent in oocysts, variable in hemocoel sporozoites, and uniform in salivary gland sporozoites, indicating developmentally regulated expression linked to infectivity.\",\n      \"method\": \"Recombinant TRAP binding assays on hepatocytes; immunofluorescence and localization studies during sporozoite development in mosquito stages\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay and localization with functional correlation to infectivity stage; single lab, two methods\",\n      \"pmids\": [\"7664729\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"TRAP (PfSSP2) localizes to sporozoite micronemes by immunoelectron microscopy and to the surface membrane by live immunofluorescence; antibodies against recombinant TRAP inhibit sporozoite invasion and development in hepatocytes in vitro.\",\n      \"method\": \"Immunoelectron microscopy; live immunofluorescence; in vitro sporozoite invasion inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to micronemes by EM plus functional inhibition; single lab, two orthogonal methods\",\n      \"pmids\": [\"1409621\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The A-domain and TSR motif of P. falciparum TRAP are both required for mosquito salivary gland invasion. Transgenic P. berghei expressing PfTRAP with a point mutation in the conserved A-domain residue or a deletion in the TSP motif showed impaired salivary gland invasion; midgut sporozoites with A-domain mutation retained motility while TSP motif deletion abolished gliding motility. Both mutants remained able to infect mice from the midgut stage.\",\n      \"method\": \"Gene replacement in P. berghei with site-directed mutant PfTRAP constructs; gliding motility assay; salivary gland invasion assay; mouse infectivity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — transgenic replacement with specific domain mutants, multiple functional readouts (motility, salivary gland invasion, mouse infectivity), clearly separating roles of each domain\",\n      \"pmids\": [\"10508153\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Loss-of-function mutations in the integrin-like A-domain and the thrombospondin type I repeat (TSR) of TRAP's ectodomain specifically decrease sporozoite invasion of host cells (mosquito salivary glands and vertebrate cells) without affecting gliding motility or cell adhesion; mutations in both modules render sporozoites non-invasive in all host cell types tested. The two adhesive modules act as independently active binding domains interacting with distinct cell receptors.\",\n      \"method\": \"Site-directed mutagenesis of TRAP ectodomain modules in P. berghei; sporozoite invasion assays in multiple cell types (mosquito salivary glands, CHO cells, human/hamster hepatoma cells); gliding motility assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-function mutagenesis with multiple host cell types and orthogonal phenotypic readouts, cleanly separating adhesion from invasion\",\n      \"pmids\": [\"11927544\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Aldolase specifically interacts with the C-terminal cytoplasmic domain of TRAP family adhesins, including TRAP; this interaction is disrupted by mutation of a critical tryptophan in the C-terminal domain previously shown to be essential for parasite motility, identifying aldolase as a bridge between TRAP and the actin cytoskeleton.\",\n      \"method\": \"Co-immunoprecipitation; pulldown assays; site-directed mutagenesis of the C-terminal tryptophan residue\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding reconstitution with mutagenesis validating critical residue; finding independently supported by structural work (PMID 17426153)\",\n      \"pmids\": [\"12718875\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The cytoplasmic tail of TRAP binds the actin-bridging protein aldolase in vitro, linking the extracellular adhesin to the actin-myosin motor complex. Homologues of glideosome-associated proteins (GAP40, GAP50) and a merozoite TRAP homologue (MTRAP) sharing TRAP's key features (thrombospondin repeat, rhomboid-protease cleavage site, aldolase-binding cytoplasmic tail) are present in P. falciparum merozoites.\",\n      \"method\": \"In vitro aldolase binding assay with TRAP cytoplasmic tail; comparative genomic and protein domain analysis; localization studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay for TRAP cytoplasmic tail-aldolase interaction; single lab\",\n      \"pmids\": [\"16321976\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"P. falciparum rhomboid protease PfROM4 cleaves TRAP in a heterologous assay, dependent on the TRAP transmembrane domain; PfROM1 also shows activity toward TRAP. This identifies rhomboid proteases as the enzymes responsible for TRAP shedding during sporozoite invasion.\",\n      \"method\": \"Heterologous rhomboid cleavage assay; transmembrane domain swap experiments establishing substrate specificity\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic assay in heterologous system with domain-swap controls; first enzymatic characterization of PfROMs on TRAP; single lab\",\n      \"pmids\": [\"17040128\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The NMR solution structure of the TSR domain of P. falciparum TRAP reveals an elongated structure stabilized by a tryptophan-arginine ladder and disulfide bonds; heparin binding maps to the N-terminal half of the TSR domain with a tetrasaccharide as the minimal binding fragment.\",\n      \"method\": \"Solution NMR structure determination; chemical shift mapping of heparin binding epitope; heparin fragment binding assays\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation of heparin binding site; single lab but rigorous structural method\",\n      \"pmids\": [\"16815922\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of P. falciparum aldolase (PfAldo) at 2.4 Å and 2.7 Å resolution with the C-terminal hexapeptide of TRAP (from P. berghei) show that the penultimate tryptophan of TRAP fits into a newly formed induced-fit hydrophobic pocket on aldolase delimited by hydrophilic residues (two arginines, one glutamate, one glutamine). Mutagenesis of PfAldo residues in and near this induced pocket reduces TRAP binding; the TRAP- and actin-binding sites on aldolase overlap.\",\n      \"method\": \"X-ray crystallography (2.4 Å and 2.7 Å); site-directed mutagenesis of aldolase residues; structural comparison with unliganded PfAldo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus mutagenesis validation; mechanistic insight into how TRAP tail engages aldolase\",\n      \"pmids\": [\"17426153\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRAP interacts with the Anopheles salivary gland protein saglin; point mutations in TRAP's A-domain binding domain abolish saglin binding, and the SM1 peptide (a mimotope of TRAP) competes for binding. In vivo knockdown of saglin strongly inhibits salivary gland invasion by Plasmodium sporozoites.\",\n      \"method\": \"UV-crosslinking of SM1 peptide to salivary gland target; anti-SM1 antibody identification of TRAP as mimotope; binding competition assays; point mutation analysis of TRAP A-domain; in vivo saglin RNAi knockdown\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (crosslinking, competition, mutagenesis, in vivo RNAi), identifying both the parasite ligand domain and the mosquito receptor\",\n      \"pmids\": [\"19148273\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of TRAP VWA and TSR domains from P. vivax and P. falciparum reveal that the VWA domain adopts closed and open conformations with Mg2+ binding at a MIDAS; in the open conformation, an extensible β-ribbon (disulfide-bonded segments flanking the VWA domain) is extended 15 Å and the TSR domain becomes ordered. The open conformation is stabilized by tensile force from the actin motility apparatus, providing a structural mechanism for 'stick-and-slip' motility regulation.\",\n      \"method\": \"X-ray crystallography (multiple crystal forms); structural comparison of closed vs. open states; identification of MIDAS metal coordination\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures in multiple lattices from two species establishing conformational switching mechanism with functional interpretation\",\n      \"pmids\": [\"23236185\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Shedding of TRAP by a rhomboid protease is essential for sporozoite gliding motility and infectivity. Mutations introduced into the TRAP rhomboid-cleavage site within the transmembrane domain resulted in defective TRAP shedding, slow staccato motility, and reduced infectivity. Mutation of both the rhomboid-cleavage site and an alternate cleavage site produced non-motile, non-infectious sporozoites, demonstrating that TRAP removal from the sporozoite surface by proteolytic shedding is required to break adhesive contacts and enable continuous forward movement.\",\n      \"method\": \"Site-directed mutagenesis of rhomboid cleavage site and alternate cleavage site in TRAP transmembrane domain in P. berghei; TRAP shedding assay; gliding motility assay; infectivity assays (intradermal and intravenous inoculation)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of cleavage sites with multiple functional readouts (shedding, motility, infectivity by two routes); mechanistically causal\",\n      \"pmids\": [\"22911675\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Gene disruption of TRAP in P. yoelii phenocopies P. berghei TRAP knockout: TRAP-null sporozoites fail to glide and cannot invade mosquito salivary glands, while erythrocytic cycle, gametocyte, and oocyst development are unaffected. Sporozoite morphology appears normal.\",\n      \"method\": \"Gene targeting by site-specific integration in P. yoelii; gliding motility assay; salivary gland invasion assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific phenotypic readouts; replicates P. berghei finding in a second rodent malaria species\",\n      \"pmids\": [\"11295181\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytoplasmic domain of TRAP can functionally substitute for the cytoplasmic domain of EBA-175 in P. falciparum merozoite invasion of erythrocytes, demonstrating that the TRAP cytoplasmic domain encodes a conserved signal recognized by the parasite's invasion machinery regardless of the invasive stage.\",\n      \"method\": \"Cytoplasmic domain swap (chimeric EBA-175 with TRAP cytoplasmic tail) in P. falciparum; erythrocyte invasion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic domain-swap with functional invasion readout; single lab\",\n      \"pmids\": [\"12876279\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Antibodies against TRAP (A-domain, conserved N-terminus, and repeat region) have no effect on sporozoite gliding motility or infectivity to mice in vivo. TRAP is normally located in micronemes and is present at very low levels on the sporozoite surface; calcium ionophore treatment or contact with hepatoma cells induces dramatic relocalization of TRAP to the parasite surface.\",\n      \"method\": \"In vivo mouse sporozoite challenge after immunization; monoclonal and polyclonal antibody gliding inhibition assays; immunofluorescence localization; calcium ionophore treatment\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result for antibody inhibition in vivo plus direct localization showing stimulus-induced surface exposure; multiple methods, single lab\",\n      \"pmids\": [\"10816526\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Recombinant P. falciparum TRAP binds to heparan sulphate proteoglycans on hepatocytes and both heparan and chondroitin sulphate proteoglycans on stellate cells; TRAP binding to Kupffer cells is glycosaminoglycan-independent.\",\n      \"method\": \"Recombinant TRAP binding assays on primary liver cells (Kupffer cells, hepatocytes, stellate cells, sinusoidal endothelia); competitive inhibition with specific glycosaminoglycans\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with recombinant protein on primary cells, cell-type-specific receptor specificity established; single lab\",\n      \"pmids\": [\"12139612\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mass spectrometry of chemically labeled P. falciparum salivary gland sporozoites provides the first direct evidence that TRAP is glycosylated on the sporozoite surface; TRAP was surface-exposed and accessible to antibodies on live sporozoites.\",\n      \"method\": \"Chemical surface labeling of live sporozoites; mass spectrometry-based proteomics; antibody accessibility assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct MS evidence of glycosylation on native protein; single lab, two complementary methods\",\n      \"pmids\": [\"27128092\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"POFUT2 (Plasmodium protein O-fucosyltransferase 2) is responsible for O-fucosylation of TRAP. Genetic disruption of POFUT2 in P. falciparum results in destabilization and incorrect trafficking of TRAP (and other TSR-bearing proteins), impairing gliding motility, cell traversal, hepatocyte invasion, and production of exoerythrocytic forms.\",\n      \"method\": \"Genetic disruption of POFUT2; assessment of TRAP stability and trafficking; gliding motility assay; cell traversal assay; hepatocyte invasion assay; humanized chimeric liver mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO identifying the writer enzyme, multiple downstream functional phenotypes established, mechanism (quality-control-dependent trafficking) proposed and supported\",\n      \"pmids\": [\"28916755\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A putative pantothenate transporter PAT is a membrane component of sporozoite micronemes and is required for secretion of TRAP-containing vesicles to the sporozoite surface; PAT-deficient P. berghei sporozoites fail to secrete TRAP, are immotile, and unable to infect the rodent host.\",\n      \"method\": \"Gene disruption of PAT in P. berghei; TRAP secretion assay; gliding motility assay; rodent infectivity assay; localization by immunofluorescence\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with TRAP secretion and motility phenotypes, mechanistically linking PAT to TRAP exocytosis; single lab\",\n      \"pmids\": [\"27427910\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRAP (together with S6) is important for initial adhesion of sporozoites to flat surfaces; total internal reflection fluorescence microscopy and flow experiments reveal that sporozoite adhesion is a multistep, developmentally regulated process in which TRAP participates in the earliest adhesion step.\",\n      \"method\": \"Total internal reflection fluorescence (TIRF) microscopy; sporozoite flow assays; genetic analysis of TRAP and S6 surface proteins\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging-based localization and adhesion assay linking TRAP to initial adhesion step; single lab\",\n      \"pmids\": [\"20159960\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-fucosylation (at Thr256) and C-mannosylation (at Trp250) of the TSR domain of P. falciparum TRAP are both individually required for TRAP protein stability and function: CRISPR/Cas9-generated glyco-null mutants (T256A and W250F) show significantly reduced TRAP protein abundance despite normal transcript levels, are unable to colonize mosquito salivary glands, and are severely impaired in gliding motility and hepatocyte invasion in vitro.\",\n      \"method\": \"CRISPR/Cas9 site-directed mutagenesis of glycosylation sites in P. falciparum TRAP; western blot quantification of TRAP protein abundance; gliding motility assay; salivary gland colonization assay; hepatocyte invasion assay; comparison with TRAP knockout line\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous site-specific mutagenesis at two glycosylation residues with multiple functional readouts and protein-level quantification; preprint but mechanistically comprehensive\",\n      \"pmids\": [\"40667256\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}]\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Transgenic P. berghei sporozoites with TRAP disrupted by gene targeting fail to glide and fail to invade mosquito salivary glands but develop normally through erythrocytic, gametocyte, and oocyst stages, directly confirming TRAP's essential role in sporozoite-stage motility.\",\n      \"method\": \"Gene targeting by homologous recombination in P. berghei; gliding motility assay; salivary gland invasion assay; blood stage and mosquito stage phenotyping\",\n      \"journal\": \"Lancet (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific motility and invasion phenotypes, consistent with PMID 9267031; reported as short communication\",\n      \"pmids\": [\"9251640\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"TRAP (PF3D7_1335900) is a type I transmembrane micronemal protein of Plasmodium sporozoites whose extracellular A-domain (von Willebrand factor-like, adopting open/closed conformations) and TSR domain bind host-cell receptors—including heparan sulfate proteoglycans on hepatocytes and the Anopheles salivary gland protein saglin—while its cytoplasmic tail is linked to the parasite actin-myosin motor via aldolase; after being translocated rearward by the motor to power gliding motility, TRAP is shed by rhomboid proteases (principally PfROM4) to break adhesive contacts and allow continuous forward movement, and this entire cycle depends on POFUT2-mediated O-fucosylation and C-mannosylation of the TSR domain for proper protein folding, ER quality-control trafficking, and stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRAP (PF3D7_1335900) is a type I transmembrane micronemal adhesin of Plasmodium sporozoites that couples host-cell recognition to the parasite's actin-myosin motor and is essential for gliding motility and productive invasion of both mosquito salivary glands and the vertebrate liver [#0, #5]. Genetic disruption in P. berghei and P. yoelii abolishes gliding and salivary-gland invasion while leaving erythrocytic, gametocyte, and oocyst development intact, defining TRAP as a sporozoite-stage motility and invasion factor [#0, #15]. Its ectodomain carries two independently active adhesive modules — an integrin-like von Willebrand factor A-domain and a thrombospondin type I repeat (TSR) — that engage distinct host receptors: the TSR binds heparin/heparan sulfate proteoglycans on hepatocytes through its N-terminal half [#10, #18], while the A-domain binds the Anopheles salivary-gland protein saglin [#12]. Structure-function mutagenesis separates roles cleanly: the two modules mediate host-cell invasion via distinct receptors, whereas the TSR is additionally required for gliding motility itself [#5, #6]. The A-domain switches between closed and open conformations coordinated by a MIDAS Mg2+ site, and force from the motor stabilizes the open state via an extensible β-ribbon, providing a structural basis for stick-and-slip motility [#13]. On the cytoplasmic side, the C-terminal tail—via a critical penultimate tryptophan that inserts into an induced-fit pocket on aldolase overlapping its actin-binding site—bridges TRAP to the actin cytoskeleton, and this tail encodes a conserved invasion signal transferable to other invasins [#7, #11, #16]. Productive motility requires proteolytic shedding of TRAP by rhomboid proteases (PfROM4, with PfROM1 activity) at a transmembrane cleavage site, which breaks rearward adhesive contacts to enable continuous forward movement [#9, #14]. The entire cycle depends on TSR glycosylation: O-fucosylation by POFUT2 and site-specific O-fucosylation (Thr256) and C-mannosylation (Trp250) are each required for TRAP folding, stability, and correct trafficking, and secretion of TRAP-containing micronemal vesicles requires the transporter PAT [#20, #21, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Before any functional data, the question was what TRAP is; molecular cloning revealed a protein carrying a thrombospondin (WSPCSVTCG) motif and an RGD adhesion motif, hinting at an adhesive function.\",\n      \"evidence\": \"Gene cloning and sequencing of P. falciparum TRAP with sequence-homology analysis\",\n      \"pmids\": [\"3045563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay beyond sequence inference\", \"Stage assignment reported as erythrocytic, later refined to sporozoite stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"To place TRAP subcellularly and test relevance to infection, immuno-EM localized it to sporozoite micronemes with stimulus-dependent surface exposure, and anti-TRAP antibodies blocked hepatocyte invasion, establishing it as an invasion-relevant surface/micronemal protein.\",\n      \"evidence\": \"Immunoelectron microscopy, live immunofluorescence, and in vitro invasion inhibition in P. falciparum\",\n      \"pmids\": [\"1409621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular receptor not identified\", \"Mechanism of surface relocalization unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"The receptor question was first addressed by showing recombinant TRAP binds sulfated glycoconjugates and hepatoma cells in a WSPCSVTCG-motif-dependent manner, defining glycosaminoglycan-type ligands as TRAP binding partners on host cells.\",\n      \"evidence\": \"Recombinant protein binding, motif-dependence and suramin/sulfatide inhibition, antisera neutralization in P. falciparum\",\n      \"pmids\": [\"8392935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native protein binding not yet shown\", \"In vivo relevance of the binding not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Whether TRAP is genuinely essential was settled by knockout in P. berghei, which abolished gliding motility, salivary-gland invasion, and liver infectivity without disrupting other life-cycle stages, defining TRAP as a dedicated sporozoite motility/invasion factor.\",\n      \"evidence\": \"Homologous-recombination knockout plus gliding and infectivity assays in P. berghei\",\n      \"pmids\": [\"9267031\", \"9251640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not distinguish adhesion from motility from invasion roles\", \"No molecular mechanism of motor coupling\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"To confirm the phenotype was not species-idiosyncratic, TRAP disruption in P. yoelii reproduced the non-gliding, non-invasive sporozoite phenotype, generalizing TRAP's essential role across rodent malaria species.\",\n      \"evidence\": \"Site-specific knockout, gliding and salivary-gland invasion assays in P. yoelii\",\n      \"pmids\": [\"11295181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address vertebrate-cell-type specificity\", \"No domain-level dissection\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The functional question of what each ectodomain module does was answered by mutagenesis showing the A-domain and TSR act as independent binding modules for distinct receptors, and that loss of both blocks invasion of all host cell types without affecting motility or adhesion.\",\n      \"evidence\": \"Site-directed mutagenesis of ectodomain modules with multi-cell-type invasion and motility assays in P. berghei; plus cell-type-specific GAG-binding of recombinant TRAP on primary liver cells\",\n      \"pmids\": [\"11927544\", \"12139612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the A-domain host receptor not yet known\", \"Cross-talk between modules unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"How the extracellular adhesin transmits force inward was addressed by identifying aldolase as the cytoplasmic-tail partner bridging TRAP to actin, dependent on a critical C-terminal tryptophan, and by showing the tail carries a transferable, conserved invasion signal.\",\n      \"evidence\": \"Co-IP, pulldown and tryptophan mutagenesis (aldolase); EBA-175/TRAP cytoplasmic domain swap in P. falciparum\",\n      \"pmids\": [\"12718875\", \"12876279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of force transmission in vivo not shown\", \"Full glideosome composition not defined here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The structural basis of the TRAP-aldolase link was resolved: the penultimate tryptophan of TRAP inserts into an induced-fit pocket on aldolase that overlaps the actin-binding site, explaining how the adhesin engages the motor.\",\n      \"evidence\": \"X-ray crystallography of PfAldo with TRAP C-terminal peptide plus aldolase mutagenesis\",\n      \"pmids\": [\"17426153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within the intact glideosome unresolved\", \"Regulation of the interaction during motility not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The TSR structure and its receptor engagement were defined by NMR, revealing a Trp-Arg-ladder/disulfide-stabilized fold with heparin binding localized to the N-terminal half, mapping the hepatocyte-receptor contact.\",\n      \"evidence\": \"NMR solution structure and heparin-fragment binding mapping of the P. falciparum TSR domain\",\n      \"pmids\": [\"16815922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full ectodomain not resolved here\", \"In vivo relevance of the minimal tetrasaccharide binding not shown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The enzymatic basis of TRAP turnover at the surface was addressed by showing rhomboid proteases PfROM4 (and PfROM1) cleave TRAP in a transmembrane-domain-dependent manner, nominating the sheddases responsible for releasing TRAP.\",\n      \"evidence\": \"Heterologous rhomboid cleavage assay with transmembrane-domain swaps\",\n      \"pmids\": [\"17040128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance shown only in heterologous system\", \"Relative in vivo contribution of PfROM4 vs PfROM1 not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To pinpoint when TRAP acts during locomotion, TIRF and flow imaging placed TRAP in the earliest adhesion step of a multistep, developmentally regulated adhesion process.\",\n      \"evidence\": \"TIRF microscopy and flow adhesion assays with TRAP and S6 mutants in P. berghei\",\n      \"pmids\": [\"20159960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular receptor for initial adhesion not identified\", \"Contribution relative to other adhesins not quantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two complementary studies answered how motility is mechanically regulated: crystal structures revealed a MIDAS-controlled closed/open A-domain switch stabilized by tensile force via an extensible β-ribbon, and cleavage-site mutagenesis showed rhomboid shedding of TRAP is required to break adhesive contacts for continuous movement.\",\n      \"evidence\": \"X-ray crystallography of VWA/TSR domains from P. vivax and P. falciparum; cleavage-site mutagenesis with shedding, motility, and infectivity assays in P. berghei\",\n      \"pmids\": [\"23236185\", \"22911675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct measurement of force-dependent conformational switching in living parasites not achieved\", \"In vivo identity of the sheddase not genetically confirmed here\"],\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The mosquito-side receptor question was answered by identifying saglin as the A-domain-binding salivary-gland partner whose knockdown blocks sporozoite invasion, defining the receptor for salivary-gland tropism.\",\n      \"evidence\": \"SM1 mimotope crosslinking, competition, A-domain point mutation, and in vivo saglin RNAi in P. falciparum\",\n      \"pmids\": [\"19148273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and structural basis of the TRAP-saglin interaction not resolved\", \"Whether saglin is the sole salivary-gland receptor unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Native-state questions were addressed by demonstrating TRAP is glycosylated and surface-exposed on live salivary-gland sporozoites, and that secretion of TRAP-containing micronemal vesicles requires the transporter PAT.\",\n      \"evidence\": \"Surface chemical labeling and mass spectrometry on live P. falciparum sporozoites; PAT knockout with TRAP secretion and motility assays in P. berghei\",\n      \"pmids\": [\"27128092\", \"27427910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycan structures not mapped at this stage\", \"Mechanism by which PAT enables microneme exocytosis unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The enzyme responsible for TRAP TSR glycosylation and its functional importance were established: POFUT2 O-fucosylates TRAP, and its loss destabilizes and mis-traffics TRAP, impairing motility, traversal, and hepatocyte invasion, linking glycosylation to ER quality control.\",\n      \"evidence\": \"POFUT2 genetic disruption with TRAP stability/trafficking, motility, traversal, invasion assays and humanized-liver mouse model in P. falciparum\",\n      \"pmids\": [\"28916755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of O-fucosylation on TRAP not pinpointed in this study\", \"Direct structural consequence of the modification on folding unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The specific glycosylation residues were dissected, showing O-fucosylation at Thr256 and C-mannosylation at Trp250 are each individually required for TRAP protein stability and for salivary-gland colonization, gliding, and hepatocyte invasion.\",\n      \"evidence\": \"CRISPR/Cas9 T256A and W250F mutants with protein-abundance quantification and functional assays in P. falciparum NF54 (preprint)\",\n      \"pmids\": [\"40667256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural mechanism by which each glycan stabilizes the TSR fold not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the A-domain force-driven conformational switch, TSR receptor engagement, rhomboid shedding, and aldolase-mediated motor coupling are temporally coordinated during a single traction cycle in the living sporozoite remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated real-time measurement of conformational state, receptor binding, and shedding during motility\", \"In vivo hierarchy of hepatocyte receptors versus saglin not established\", \"Structural basis of the TRAP-saglin interaction unknown\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0050839\", \"supporting_discovery_ids\": [2, 3, 10, 12, 18]},\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0005178\", \"supporting_discovery_ids\": [6, 22]},\n      {\"term_id\": \"GO:0046872\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [4, 17, 21, 22]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [4, 17, 19, 22]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0048870\", \"supporting_discovery_ids\": [0, 5, 6, 14, 15, 24]},\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [0, 3, 5, 6, 12, 15]},\n      {\"term_id\": \"GO:0006486\", \"supporting_discovery_ids\": [19, 20, 23]}\n    ],\n    \"complexes\": [\n      \"Glideosome / actin-myosin motor complex (linked via aldolase to the TRAP cytoplasmic tail)\"\n    ],\n    \"partners\": [\n      \"Aldolase (PfAldo) — binds TRAP C-terminal cytoplasmic tail, bridging to actin [#7, #8, #11]\",\n      \"Heparan sulfate / sulfated glycoconjugate proteoglycans on hepatocytes — TSR ligand [#2, #3, #10, #18]\",\n      \"Chondroitin sulfate proteoglycans on stellate cells [#18]\",\n      \"Saglin (Anopheles salivary gland protein) — A-domain receptor [#12]\",\n      \"PfROM4 / PfROM1 rhomboid proteases — cleave/shed TRAP [#9, #14]\",\n      \"POFUT2 O-fucosyltransferase — modifies TRAP TSR [#20, #23]\",\n      \"PAT putative pantothenate transporter — required for TRAP micronemal secretion [#21]\",\n      \"S6 — co-participant in early sporozoite adhesion [#22]\"\n    ],\n    \"other_free_text\": [\n      \"Type I transmembrane micronemal adhesin of Plasmodium sporozoites; extracellular region contains an integrin-like von Willebrand factor A-domain and a thrombospondin type I repeat (TSR) [#1, #6, #10].\",\n      \"A-domain adopts closed and open conformations with Mg2+ at a MIDAS; the open state is stabilized by tensile force via an extensible β-ribbon, supporting a stick-and-slip motility mechanism [#13].\",\n      \"TSR fold stabilized by a tryptophan-arginine ladder and disulfide bonds; heparin binding maps to the N-terminal half with a tetrasaccharide as minimal ligand [#10].\",\n      \"Cytoplasmic tail carries a conserved invasion signal transferable to EBA-175, and engages aldolase through a penultimate tryptophan inserted into an induced-fit pocket overlapping aldolase's actin-binding site [#7, #11, #16].\",\n      \"TSR is post-translationally modified by O-fucosylation (Thr256) and C-mannosylation (Trp250), each required for TRAP stability and function [#20, #23].\",\n      \"Developmentally regulated expression: absent in oocysts, uniform in salivary-gland sporozoites; low surface levels with calcium- or host-cell-contact-induced surface relocalization [#3, #17].\",\n      \"Knockout in P. berghei and P. yoelii abolishes gliding and salivary-gland invasion while sparing blood, gametocyte and oocyst stages [#0, #15, #24].\",\n      \"Anti-TRAP antibodies inhibit hepatocyte invasion in vitro but did not affect gliding/infectivity in vivo in one P. yoelii study [#2, #4, #17].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1335900","name":null,"product":"thrombospondin-related anonymous protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1349800","name":null,"product":"thrombospondin-related anonymous protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1265400","name":null,"product":"thrombospondin-related anonymous protein","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"TRAP","evaluation":null}