{"gene":"PF3D7_1147800","run_date":"2026-09-08T14:19:05","timeline":{"discoveries":[{"year":1998,"finding":"MAEBL (PF3D7_1147800 orthologues in P. yoelii and P. berghei) has a chimeric domain structure: its N-terminal cysteine-rich domain is similar to AMA-1 domains I/II (not to Duffy binding-like domains), and its C-terminal region is homologous to the EBL family. Both tandem AMA-1-like domains (M1 and M2) bound erythrocytes when expressed in vitro. The apical distribution of MAEBL suggested localization within rhoptry organelles.","method":"In vitro erythrocyte-binding assay of recombinant domains expressed in COS cells; sequence/domain analysis; indirect immunofluorescence assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay with expressed domains plus IFA localization, single lab, two orthogonal methods","pmids":["9448314"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii yoelii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":1998,"finding":"In P. yoelii YM, MAEBL co-localizes with rhoptry proteins (AMA-1 and the 235 kDa rhoptry proteins) by immunofluorescence, and is expressed early in schizont development before appearing on the merozoite surface after segmentation. The protein immunoprecipitates as a doublet (~120/128 kDa) and is insoluble compared to DBL-EBP family members.","method":"Indirect immunofluorescence co-localization; immunoprecipitation; Western blot","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization IFA and immunoprecipitation, single lab, two orthogonal methods","pmids":["9851604"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":"YM"}]},{"year":2000,"finding":"In P. yoelii, MAEBL transits through the classical secretory pathway (ER tubular network → Golgi bodies positioned near the plasma membrane → rhoptry precursor organelles) during schizogony. MAEBL and MSP-1 co-localized in the transient tubular ER network at the onset of schizogony.","method":"Live and fixed immunofluorescence microscopy; co-localization with ER markers and Golgi markers during schizont differentiation","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by imaging with functional context (secretory pathway), single lab, multiple time-point analysis","pmids":["10838220"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2002,"finding":"Targeted disruption of the P. berghei MAEBL gene demonstrated that MAEBL is essential for sporozoite infection of the mosquito salivary gland and is involved in attachment to the salivary gland surface. MAEBL disruption did not affect sporozoite motility in vitro or infectivity to the vertebrate host. MAEBL was localized to the micronemes of oocyst sporozoites.","method":"Targeted gene disruption (knockout); salivary gland invasion assay; in vitro motility assay; immunofluorescence localization","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with specific phenotypic readout (salivary gland invasion), IFA localization, multiple orthogonal methods, replicated in concept by later studies","pmids":["12021311"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2002,"finding":"In P. falciparum, MAEBL localizes with rhoptry proteins (RhopH2, RAP-1) in mature merozoites and shows surface co-localization with RhopH2, but does not co-localize with microneme proteins (EBA-175, BAEBL). MAEBL appears as proteolytically processed fragments: the amino cysteine-rich ligand domains are shed into culture supernatants, while the carboxyl domain adjacent to the transmembrane region is retained in Triton X-100 fractions.","method":"Indirect immunofluorescence co-localization; Western blot of fractionated parasite material (culture supernatant vs. detergent-extracted fractions)","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-localization IFA and biochemical fractionation, single lab, two orthogonal methods","pmids":["12076768"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"The recombinant M2 domain of P. falciparum MAEBL (r-PfM2) binds human erythrocytes; binding is abolished by papain pretreatment but increased by neuraminidase treatment, indicating dependence on a protease-sensitive, sialic acid-independent receptor. Polyclonal antibodies to r-PfM2 recognize native MAEBL in schizont extracts and localize it within the apical complex of free merozoites.","method":"Recombinant protein expression (E. coli); in vitro erythrocyte binding assay with enzyme treatments; Western blot; indirect immunofluorescence assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay with receptor-enzyme dissection plus IFA, single lab, multiple orthogonal methods","pmids":["12165387"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"In P. berghei, MAEBL subcellular distribution is developmentally regulated during sporozoite maturation in oocysts: in day-15 oocysts MAEBL is in presumed storage organelles, whereas in day-22 oocysts it redistributes to a uniform surface distribution, consistent with a role in salivary gland invasion.","method":"Immunofluorescence microscopy at defined time-points during oocyst differentiation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization imaging at multiple developmental stages, single lab","pmids":["14627711"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2004,"finding":"In salivary gland sporozoites, MAEBL is newly expressed in a form distinct from midgut sporozoite and erythrocytic stage forms: it includes both M1 and M2 ligand domains as part of a full-length membrane protein, whereas other stages retain only the M2 domain in the membrane form. Antisera against the M1 and M2 cysteine-rich extracellular regions of MAEBL inhibited sporozoite development to exoerythrocytic forms in vitro.","method":"Western blot analysis of stage-specific MAEBL isoforms; in vitro inhibition assay of sporozoite development to exoerythrocytic forms using anti-M1/M2 antisera","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical isoform characterization plus functional inhibition assay, single lab, two orthogonal methods","pmids":["15155670"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2004,"finding":"Synthetic peptides spanning the P. falciparum MAEBL sequence identified nine high-activity erythrocyte-binding peptides (HABPs): two in M1, one between M1 and M2, five in M2, and one in the repeat region. Several HABPs inhibited in vitro merozoite invasion of erythrocytes and specifically bound a 33 kDa protein on the red blood cell membrane.","method":"Synthetic peptide erythrocyte-binding assays; in vitro merozoite invasion inhibition assay; RBC membrane protein binding identification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding and invasion inhibition assays, single lab, single study","pmids":["14766210"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"Alternative splicing of the maebl locus is conserved across multiple Plasmodium species and is developmentally controlled. The major alternatively spliced transcript uses a less favorable acceptor splice site, shifting the coding sequence to produce a predicted soluble isoform lacking the transmembrane domain, whereas the canonical transcript encodes the type I membrane protein. Western blot analysis showed MAEBL protein expression correlates better with the canonical ORF1 transcript.","method":"RT-PCR; Western blot; sequence analysis of splice variants across multiple Plasmodium species","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RT-PCR and Western blot across multiple species, single lab, two orthogonal methods","pmids":["15465047"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium yoelii","strain":""}]},{"year":2005,"finding":"Targeted disruption of maebl in P. falciparum was achieved, establishing that blood-stage MAEBL is not essential for erythrocytic growth in vitro.","method":"Targeted gene disruption (knockout) in P. falciparum","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic knockout, single lab; abstract only (no detailed methods available)","pmids":["15811533"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PfROM4 (a P. falciparum rhomboid intramembrane protease) cleaves MAEBL efficiently in a heterologous processing assay, and this cleavage depends on the MAEBL transmembrane domain. PfROM1 did not cleave MAEBL in this assay.","method":"Heterologous rhomboid cleavage assay; transmembrane domain swap experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with substrate mutagenesis (TM domain swaps), single lab but rigorous biochemical reconstitution","pmids":["17040128"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Only the transmembrane isoform of P. falciparum MAEBL is essential for sporozoite invasion of Anopheles salivary glands. Knockout parasites and allelic replacement parasites expressing only the soluble isoform failed to invade salivary glands, whereas those expressing only the transmembrane isoform retained invasion ability.","method":"Targeted gene knockout and allelic replacement with single-isoform constructs in P. falciparum (NF54); salivary gland invasion assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic dissection with isoform-specific allelic replacements, clear functional readout, replicated across multiple transgenic lines","pmids":["18509478"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":2008,"finding":"The P. falciparum maebl transcript has an exceptionally long 5'-UTR (>2 kb) containing a small multi-exon ORF (PF11_0485, annotated as putative mitochondrial ATP synthase), forming a bicistronic mRNA. The minimal maebl promoter lies upstream of PF11_0485, as determined by CAT reporter assays.","method":"Northern blot; RT-PCR; 5'-RACE; transient CAT reporter assay","journal":"Experimental parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transcript mapping methods plus functional promoter assay, single lab","pmids":["18950624"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"MAEBL-deficient P. falciparum sporozoites are severely attenuated for cell traversal activity and hepatocyte entry in vitro, and for liver infection in humanized chimeric liver mice. Genetic complementation of MAEBL-deficient parasites restored infectivity. MAEBL therefore plays an essential role in sporozoite cell traversal and hepatocyte invasion, distinct from its role in salivary gland invasion.","method":"MAEBL gene knockout in P. falciparum; in vitro cell traversal assay; hepatocyte invasion assay; in vivo humanized chimeric liver mouse infection model; genetic complementation","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with genetic complementation, multiple orthogonal functional assays (in vitro and in vivo), single lab","pmids":["28371168"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"In P. berghei, absence of MAEBL reduces hemolymph sporozoite infectivity to mice and impairs sporozoite adhesion to cultured hepatocytes, contributing to defects in gliding motility, hepatocyte wounding, and invasion. MAEBL was found associated with micronemes and also with the surface of mature sporozoites. MAEBL levels peak in midgut and hemolymph sporozoites but drop after entry into salivary glands, where labeling is heterogeneous. Genetic complementation reversed the salivary gland and liver infection defects.","method":"Transgenic knockout and complemented parasites; live imaging in mice; in vitro hepatocyte adhesion/invasion assays; IFA with C-terminal myc-tagged MAEBL; gliding motility assay; hepatocyte wounding assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with complementation, multiple orthogonal functional assays, direct tagged-protein localization","pmids":["35628522"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"MAEBL (PF3D7_1147800) is a type I transmembrane, chimeric erythrocyte-binding protein expressed in multiple Plasmodium life cycle stages: it localizes to rhoptries in merozoites (where its shed M1/M2 AMA-1-like domains mediate erythrocyte binding via a papain-sensitive, sialic acid-independent receptor and its transmembrane domain is a substrate for cleavage by PfROM4), and to micronemes/surface of sporozoites (where the transmembrane isoform is essential for attachment to and invasion of mosquito salivary glands, for cell traversal, and for hepatocyte invasion during liver-stage infection); its expression and isoform composition are developmentally regulated through alternative splicing and a bicistronic transcript architecture."},"narrative":{"mechanistic_narrative":"MAEBL (PF3D7_1147800) is a type I transmembrane, chimeric erythrocyte-binding protein that acts as an adhesive ligand across multiple Plasmodium life-cycle stages [PMID:9448314, PMID:12021311, PMID:28371168]. Its ectodomain is a mosaic in which an N-terminal cysteine-rich region resembles AMA-1 domains I/II arranged as two tandem ligand modules (M1 and M2), while its C-terminal region is homologous to the EBL family [PMID:9448314]. Both AMA-1-like domains bind erythrocytes in vitro, and the M2 domain engages a papain-sensitive, sialic acid-independent red-cell receptor [PMID:9448314, PMID:12165387]. In merozoites, MAEBL transits the classical secretory pathway to rhoptry organelles and co-localizes with rhoptry proteins, where it is proteolytically processed such that the amino cysteine-rich ligand domains are shed while the transmembrane-proximal carboxyl domain is retained; its transmembrane segment is an efficient and selective substrate for the intramembrane rhomboid protease PfROM4 but not PfROM1 [PMID:10838220, PMID:12076768, PMID:17040128]. Blood-stage MAEBL is dispensable for erythrocytic growth in vitro [PMID:15811533]. In sporozoites the protein localizes to micronemes and the parasite surface and is essential for attachment to and invasion of the mosquito salivary gland, an activity that requires specifically the transmembrane isoform [PMID:12021311, PMID:18509478, PMID:35628522]. MAEBL additionally mediates sporozoite cell traversal, hepatocyte adhesion, and liver-stage invasion, phenotypes rescued by genetic complementation [PMID:28371168, PMID:35628522]. Its expression and isoform composition are developmentally controlled through conserved alternative splicing that toggles between membrane-bound and predicted soluble forms, and through a bicistronic transcript architecture with an exceptionally long 5'-UTR harboring an upstream ORF [PMID:15155670, PMID:15465047, PMID:18950624].","teleology":[{"year":1998,"claim":"Establishing that MAEBL is a chimeric adhesin answered what kind of ligand it is: an AMA-1/EBL mosaic whose tandem AMA-1-like domains, not Duffy-binding-like domains, mediate erythrocyte binding.","evidence":"In vitro erythrocyte-binding of recombinant M1/M2 domains expressed in COS cells with sequence/domain analysis and IFA, in P. yoelii and P. berghei orthologues","pmids":["9448314"],"confidence":"Medium","gaps":["Native receptor on the erythrocyte not identified","Binding of full-length native protein versus isolated domains not established"],"attribution":[{"species":"Plasmodium yoelii yoelii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":1998,"claim":"Co-localization with rhoptry markers and timing of appearance placed MAEBL in the merozoite apical secretory machinery, distinguishing it biochemically from soluble DBL-EBP adhesins.","evidence":"IFA co-localization with AMA-1 and 235 kDa rhoptry proteins, immunoprecipitation and Western blot in P. yoelii YM","pmids":["9851604"],"confidence":"Medium","gaps":["Functional role in the rhoptry not tested","Basis of the ~120/128 kDa doublet not defined"],"attribution":[{"species":"Plasmodium yoelii","strain":"YM"}]},{"year":2000,"claim":"Tracing MAEBL through ER, Golgi, and rhoptry precursors defined its trafficking route to the apical organelles during schizogony.","evidence":"Live and fixed IFA with ER and Golgi markers across schizont differentiation in P. yoelii","pmids":["10838220"],"confidence":"Medium","gaps":["Trafficking signals/sorting determinants not mapped","Single-species observation"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2002,"claim":"Knockout in P. berghei answered which life-cycle step requires MAEBL, showing it is essential for sporozoite invasion of the mosquito salivary gland but dispensable for motility and vertebrate infectivity as assayed.","evidence":"Targeted gene disruption with salivary gland invasion and motility assays plus microneme IFA in P. berghei","pmids":["12021311"],"confidence":"High","gaps":["Salivary gland receptor for MAEBL unknown","Mechanistic step of attachment versus invasion not separated"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2002,"claim":"Reciprocal co-localization and fractionation in P. falciparum showed MAEBL associates with rhoptry (not microneme) proteins in merozoites and is processed so ligand domains are shed while the membrane-proximal domain is retained.","evidence":"IFA co-localization with RhopH2/RAP-1 versus EBA-175/BAEBL and Western blot of supernatant versus detergent fractions in P. falciparum","pmids":["12076768"],"confidence":"Medium","gaps":["Protease responsible for ectodomain shedding not identified here","Functional consequence of shedding untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"claim":"Enzymatic dissection of M2-domain binding defined the receptor as protease-sensitive and sialic-acid-independent, refining the biochemical nature of MAEBL-erythrocyte engagement.","evidence":"Recombinant PfM2 erythrocyte-binding assay with papain/neuraminidase treatments plus IFA in P. falciparum","pmids":["12165387"],"confidence":"Medium","gaps":["Molecular identity of the receptor not determined","Only M2 tested for receptor properties"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Stage-resolved imaging showed MAEBL redistributes from storage organelles to the sporozoite surface as oocysts mature, linking its relocation to acquisition of salivary-gland invasiveness.","evidence":"IFA at defined oocyst developmental time-points in P. berghei","pmids":["14627711"],"confidence":"Medium","gaps":["Trigger for redistribution unknown","Correlative rather than causal link to invasion"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2004,"claim":"Isoform mapping revealed that salivary gland sporozoites uniquely express a full-length membrane form retaining both M1 and M2 domains, and antibodies to these domains block sporozoite development, implicating the ligand domains functionally.","evidence":"Stage-specific Western blots and antibody inhibition of exoerythrocytic development in P. berghei","pmids":["15155670"],"confidence":"Medium","gaps":["Direct target of the inhibitory antisera in the invasion pathway not defined","Whether M1 and M2 have distinct functions unresolved"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2004,"claim":"Peptide scanning localized erythrocyte-binding activity to discrete high-activity regions across M1, M2, and the repeat region and tied binding to a 33 kDa red-cell membrane protein.","evidence":"Synthetic peptide binding assays, merozoite invasion inhibition, and RBC membrane protein binding in P. falciparum","pmids":["14766210"],"confidence":"Medium","gaps":["33 kDa RBC protein not identified","Peptide-level binding may not reflect native domain architecture"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"claim":"Discovery of conserved, developmentally controlled alternative splicing showed the maebl locus can produce either the type I membrane protein or a predicted soluble isoform, providing a regulatory switch over MAEBL form.","evidence":"RT-PCR, Western blot, and splice-variant sequence analysis across P. falciparum, P. berghei, and P. yoelii","pmids":["15465047"],"confidence":"Medium","gaps":["Regulators of splice-site choice unknown","Function of the soluble isoform not directly tested here"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium yoelii","strain":""}]},{"year":2005,"claim":"Knockout in P. falciparum established that blood-stage MAEBL is not required for erythrocytic growth in vitro, narrowing its essential roles to other stages.","evidence":"Targeted gene disruption in P. falciparum (abstract-level)","pmids":["15811533"],"confidence":"Medium","gaps":["Abstract only, limited methodological detail","Possible redundancy with other invasion ligands not examined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Identifying MAEBL as a selective PfROM4 substrate provided a molecular mechanism for membrane release/processing, dependent on the MAEBL transmembrane domain.","evidence":"Heterologous rhomboid cleavage assay with transmembrane-domain swaps in P. falciparum","pmids":["17040128"],"confidence":"High","gaps":["In vivo timing and requirement of PfROM4 cleavage of MAEBL not shown","Functional consequence of cleavage for invasion untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Isoform-specific allelic replacement demonstrated that only the transmembrane MAEBL isoform supports salivary gland invasion, assigning function to a specific molecular form.","evidence":"Knockout and single-isoform allelic replacement with salivary gland invasion assays in P. falciparum NF54","pmids":["18509478"],"confidence":"High","gaps":["Role, if any, of the soluble isoform not defined","Molecular partner engaged by the transmembrane form unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":2008,"claim":"Mapping the maebl mRNA revealed a bicistronic architecture with a >2 kb 5'-UTR containing an upstream ORF and an upstream minimal promoter, defining an unusual transcriptional/translational control layer.","evidence":"Northern blot, RT-PCR, 5'-RACE, and transient CAT reporter assays in P. falciparum","pmids":["18950624"],"confidence":"Medium","gaps":["Regulatory function of the upstream ORF not established","Translational control mechanism not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Knockout with complementation in P. falciparum uncovered a distinct essential role for MAEBL in sporozoite cell traversal and hepatocyte invasion, extending its function beyond salivary gland entry into liver-stage infection.","evidence":"Gene knockout with genetic complementation, cell traversal and hepatocyte invasion assays, and humanized chimeric liver mouse infection in P. falciparum","pmids":["28371168"],"confidence":"High","gaps":["Hepatocyte receptor/ligand for MAEBL not identified","Mechanistic distinction between traversal and productive invasion not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Knockout/complementation in P. berghei consolidated MAEBL's role in hepatocyte adhesion, gliding motility, wounding, and invasion, and showed stage-dependent surface/microneme localization with declining levels after salivary gland entry.","evidence":"Transgenic knockout and complemented parasites, live mouse imaging, hepatocyte adhesion/invasion, gliding and wounding assays, and myc-tagged MAEBL IFA in P. berghei","pmids":["35628522"],"confidence":"High","gaps":["Molecular basis of adhesion to hepatocytes unknown","Cause of post-salivary-gland decline in MAEBL not defined"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The molecular identities of the MAEBL receptors on erythrocytes, mosquito salivary glands, and hepatocytes, and the in vivo role of PfROM4 cleavage, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No host receptor for any MAEBL-dependent invasion step has been molecularly identified","In vivo functional requirement and timing of PfROM4 processing of MAEBL untested","Function of the soluble spliced isoform undefined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFROM4 (RHOMBOID INTRAMEMBRANE PROTEASE THAT CLEAVES MAEBL; PFROM1 DOES NOT) [#11]"],"other_free_text":["Chimeric domain architecture: N-terminal cysteine-rich AMA-1-like domains (tandem M1 and M2), plus a C-terminal EBL-family-homologous region [#0].","M2 domain binds a papain-sensitive, sialic-acid-independent erythrocyte receptor; high-activity binding peptides span M1, M2, and the repeat region and engage a 33 kDa RBC membrane protein [#5, #8].","Merozoite MAEBL is processed so amino ligand domains are shed while the transmembrane-proximal carboxyl domain is retained in detergent fractions [#4].","Only the transmembrane isoform supports mosquito salivary gland invasion; a predicted soluble isoform is generated by conserved developmentally controlled alternative splicing [#9, #12].","maebl is encoded on a bicistronic mRNA with a >2 kb 5'-UTR containing an upstream small ORF (PF11_0485) and the minimal promoter [#13].","Blood-stage MAEBL is dispensable for erythrocytic growth in vitro; sporozoite roles in salivary gland invasion, cell traversal, and hepatocyte invasion are essential and complementable [#10, #12, #14, #15]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"17040128","id":"PMC_17040128","title":"Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria.","date":"2006","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/17040128","citation_count":180,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12021311","id":"PMC_12021311","title":"MAEBL is essential for malarial sporozoite infection of the mosquito salivary gland.","date":"2002","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12021311","citation_count":97,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9448314","id":"PMC_9448314","title":"A family of chimeric erythrocyte binding proteins of malaria parasites.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9448314","citation_count":94,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16154214","id":"PMC_16154214","title":"Structural comparison of apical membrane antigen 1 orthologues and paralogues in apicomplexan parasites.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/16154214","citation_count":82,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12000842","id":"PMC_12000842","title":"Transcripts of developmentally regulated Plasmodium falciparum genes quantified by real-time RT-PCR.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12000842","citation_count":66,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"14627711","id":"PMC_14627711","title":"Analysis of the Plasmodium and Anopheles transcriptomes during oocyst differentiation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14627711","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11551631","id":"PMC_11551631","title":"Erythrocyte-binding activity of Plasmodium yoelii apical membrane antigen-1 expressed on the surface of transfected COS-7 cells.","date":"2001","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/11551631","citation_count":55,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MAEBL"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11027815","id":"PMC_11027815","title":"Plasmodium falciparum AMA-1 erythrocyte binding peptides implicate AMA-1 as erythrocyte binding 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C-terminal region is homologous to the EBL family. Both tandem AMA-1-like domains (M1 and M2) bound erythrocytes when expressed in vitro. The apical distribution of MAEBL suggested localization within rhoptry organelles.\",\n      \"method\": \"In vitro erythrocyte-binding assay of recombinant domains expressed in COS cells; sequence/domain analysis; indirect immunofluorescence 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 — in vitro binding assay with expressed domains plus IFA localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"9448314\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii yoelii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In P. yoelii YM, MAEBL co-localizes with rhoptry proteins (AMA-1 and the 235 kDa rhoptry proteins) by immunofluorescence, and is expressed early in schizont development before appearing on the merozoite surface after segmentation. The protein immunoprecipitates as a doublet (~120/128 kDa) and is insoluble compared to DBL-EBP family members.\",\n      \"method\": \"Indirect immunofluorescence co-localization; immunoprecipitation; Western blot\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization IFA and immunoprecipitation, single lab, two orthogonal methods\",\n      \"pmids\": [\"9851604\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"YM\"}\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In P. yoelii, MAEBL transits through the classical secretory pathway (ER tubular network → Golgi bodies positioned near the plasma membrane → rhoptry precursor organelles) during schizogony. MAEBL and MSP-1 co-localized in the transient tubular ER network at the onset of schizogony.\",\n      \"method\": \"Live and fixed immunofluorescence microscopy; co-localization with ER markers and Golgi markers during schizont differentiation\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by imaging with functional context (secretory pathway), single lab, multiple time-point analysis\",\n      \"pmids\": [\"10838220\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted disruption of the P. berghei MAEBL gene demonstrated that MAEBL is essential for sporozoite infection of the mosquito salivary gland and is involved in attachment to the salivary gland surface. MAEBL disruption did not affect sporozoite motility in vitro or infectivity to the vertebrate host. MAEBL was localized to the micronemes of oocyst sporozoites.\",\n      \"method\": \"Targeted gene disruption (knockout); salivary gland invasion assay; in vitro motility assay; immunofluorescence localization\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with specific phenotypic readout (salivary gland invasion), IFA localization, multiple orthogonal methods, replicated in concept by later studies\",\n      \"pmids\": [\"12021311\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In P. falciparum, MAEBL localizes with rhoptry proteins (RhopH2, RAP-1) in mature merozoites and shows surface co-localization with RhopH2, but does not co-localize with microneme proteins (EBA-175, BAEBL). MAEBL appears as proteolytically processed fragments: the amino cysteine-rich ligand domains are shed into culture supernatants, while the carboxyl domain adjacent to the transmembrane region is retained in Triton X-100 fractions.\",\n      \"method\": \"Indirect immunofluorescence co-localization; Western blot of fractionated parasite material (culture supernatant vs. detergent-extracted fractions)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-localization IFA and biochemical fractionation, single lab, two orthogonal methods\",\n      \"pmids\": [\"12076768\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The recombinant M2 domain of P. falciparum MAEBL (r-PfM2) binds human erythrocytes; binding is abolished by papain pretreatment but increased by neuraminidase treatment, indicating dependence on a protease-sensitive, sialic acid-independent receptor. Polyclonal antibodies to r-PfM2 recognize native MAEBL in schizont extracts and localize it within the apical complex of free merozoites.\",\n      \"method\": \"Recombinant protein expression (E. coli); in vitro erythrocyte binding assay with enzyme treatments; Western blot; indirect immunofluorescence assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay with receptor-enzyme dissection plus IFA, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12165387\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In P. berghei, MAEBL subcellular distribution is developmentally regulated during sporozoite maturation in oocysts: in day-15 oocysts MAEBL is in presumed storage organelles, whereas in day-22 oocysts it redistributes to a uniform surface distribution, consistent with a role in salivary gland invasion.\",\n      \"method\": \"Immunofluorescence microscopy at defined time-points during oocyst differentiation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization imaging at multiple developmental stages, single lab\",\n      \"pmids\": [\"14627711\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In salivary gland sporozoites, MAEBL is newly expressed in a form distinct from midgut sporozoite and erythrocytic stage forms: it includes both M1 and M2 ligand domains as part of a full-length membrane protein, whereas other stages retain only the M2 domain in the membrane form. Antisera against the M1 and M2 cysteine-rich extracellular regions of MAEBL inhibited sporozoite development to exoerythrocytic forms in vitro.\",\n      \"method\": \"Western blot analysis of stage-specific MAEBL isoforms; in vitro inhibition assay of sporozoite development to exoerythrocytic forms using anti-M1/M2 antisera\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical isoform characterization plus functional inhibition assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"15155670\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Synthetic peptides spanning the P. falciparum MAEBL sequence identified nine high-activity erythrocyte-binding peptides (HABPs): two in M1, one between M1 and M2, five in M2, and one in the repeat region. Several HABPs inhibited in vitro merozoite invasion of erythrocytes and specifically bound a 33 kDa protein on the red blood cell membrane.\",\n      \"method\": \"Synthetic peptide erythrocyte-binding assays; in vitro merozoite invasion inhibition assay; RBC membrane protein binding identification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding and invasion inhibition assays, single lab, single study\",\n      \"pmids\": [\"14766210\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Alternative splicing of the maebl locus is conserved across multiple Plasmodium species and is developmentally controlled. The major alternatively spliced transcript uses a less favorable acceptor splice site, shifting the coding sequence to produce a predicted soluble isoform lacking the transmembrane domain, whereas the canonical transcript encodes the type I membrane protein. Western blot analysis showed MAEBL protein expression correlates better with the canonical ORF1 transcript.\",\n      \"method\": \"RT-PCR; Western blot; sequence analysis of splice variants across multiple Plasmodium species\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RT-PCR and Western blot across multiple species, single lab, two orthogonal methods\",\n      \"pmids\": [\"15465047\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Targeted disruption of maebl in P. falciparum was achieved, establishing that blood-stage MAEBL is not essential for erythrocytic growth in vitro.\",\n      \"method\": \"Targeted gene disruption (knockout) in P. falciparum\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic knockout, single lab; abstract only (no detailed methods available)\",\n      \"pmids\": [\"15811533\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PfROM4 (a P. falciparum rhomboid intramembrane protease) cleaves MAEBL efficiently in a heterologous processing assay, and this cleavage depends on the MAEBL transmembrane domain. PfROM1 did not cleave MAEBL in this assay.\",\n      \"method\": \"Heterologous rhomboid cleavage assay; transmembrane domain swap experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with substrate mutagenesis (TM domain swaps), single lab but rigorous biochemical reconstitution\",\n      \"pmids\": [\"17040128\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Only the transmembrane isoform of P. falciparum MAEBL is essential for sporozoite invasion of Anopheles salivary glands. Knockout parasites and allelic replacement parasites expressing only the soluble isoform failed to invade salivary glands, whereas those expressing only the transmembrane isoform retained invasion ability.\",\n      \"method\": \"Targeted gene knockout and allelic replacement with single-isoform constructs in P. falciparum (NF54); salivary gland invasion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic dissection with isoform-specific allelic replacements, clear functional readout, replicated across multiple transgenic lines\",\n      \"pmids\": [\"18509478\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The P. falciparum maebl transcript has an exceptionally long 5'-UTR (>2 kb) containing a small multi-exon ORF (PF11_0485, annotated as putative mitochondrial ATP synthase), forming a bicistronic mRNA. The minimal maebl promoter lies upstream of PF11_0485, as determined by CAT reporter assays.\",\n      \"method\": \"Northern blot; RT-PCR; 5'-RACE; transient CAT reporter assay\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transcript mapping methods plus functional promoter assay, single lab\",\n      \"pmids\": [\"18950624\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAEBL-deficient P. falciparum sporozoites are severely attenuated for cell traversal activity and hepatocyte entry in vitro, and for liver infection in humanized chimeric liver mice. Genetic complementation of MAEBL-deficient parasites restored infectivity. MAEBL therefore plays an essential role in sporozoite cell traversal and hepatocyte invasion, distinct from its role in salivary gland invasion.\",\n      \"method\": \"MAEBL gene knockout in P. falciparum; in vitro cell traversal assay; hepatocyte invasion assay; in vivo humanized chimeric liver mouse infection model; genetic complementation\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with genetic complementation, multiple orthogonal functional assays (in vitro and in vivo), single lab\",\n      \"pmids\": [\"28371168\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In P. berghei, absence of MAEBL reduces hemolymph sporozoite infectivity to mice and impairs sporozoite adhesion to cultured hepatocytes, contributing to defects in gliding motility, hepatocyte wounding, and invasion. MAEBL was found associated with micronemes and also with the surface of mature sporozoites. MAEBL levels peak in midgut and hemolymph sporozoites but drop after entry into salivary glands, where labeling is heterogeneous. Genetic complementation reversed the salivary gland and liver infection defects.\",\n      \"method\": \"Transgenic knockout and complemented parasites; live imaging in mice; in vitro hepatocyte adhesion/invasion assays; IFA with C-terminal myc-tagged MAEBL; gliding motility assay; hepatocyte wounding assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with complementation, multiple orthogonal functional assays, direct tagged-protein localization\",\n      \"pmids\": [\"35628522\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"MAEBL (PF3D7_1147800) is a type I transmembrane, chimeric erythrocyte-binding protein expressed in multiple Plasmodium life cycle stages: it localizes to rhoptries in merozoites (where its shed M1/M2 AMA-1-like domains mediate erythrocyte binding via a papain-sensitive, sialic acid-independent receptor and its transmembrane domain is a substrate for cleavage by PfROM4), and to micronemes/surface of sporozoites (where the transmembrane isoform is essential for attachment to and invasion of mosquito salivary glands, for cell traversal, and for hepatocyte invasion during liver-stage infection); its expression and isoform composition are developmentally regulated through alternative splicing and a bicistronic transcript architecture.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAEBL (PF3D7_1147800) is a type I transmembrane, chimeric erythrocyte-binding protein that acts as an adhesive ligand across multiple Plasmodium life-cycle stages [#0, #3, #14]. Its ectodomain is a mosaic in which an N-terminal cysteine-rich region resembles AMA-1 domains I/II arranged as two tandem ligand modules (M1 and M2), while its C-terminal region is homologous to the EBL family [#0]. Both AMA-1-like domains bind erythrocytes in vitro, and the M2 domain engages a papain-sensitive, sialic acid-independent red-cell receptor [#0, #5]. In merozoites, MAEBL transits the classical secretory pathway to rhoptry organelles and co-localizes with rhoptry proteins, where it is proteolytically processed such that the amino cysteine-rich ligand domains are shed while the transmembrane-proximal carboxyl domain is retained; its transmembrane segment is an efficient and selective substrate for the intramembrane rhomboid protease PfROM4 but not PfROM1 [#2, #4, #11]. Blood-stage MAEBL is dispensable for erythrocytic growth in vitro [#10]. In sporozoites the protein localizes to micronemes and the parasite surface and is essential for attachment to and invasion of the mosquito salivary gland, an activity that requires specifically the transmembrane isoform [#3, #12, #15]. MAEBL additionally mediates sporozoite cell traversal, hepatocyte adhesion, and liver-stage invasion, phenotypes rescued by genetic complementation [#14, #15]. Its expression and isoform composition are developmentally controlled through conserved alternative splicing that toggles between membrane-bound and predicted soluble forms, and through a bicistronic transcript architecture with an exceptionally long 5'-UTR harboring an upstream ORF [#7, #9, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that MAEBL is a chimeric adhesin answered what kind of ligand it is: an AMA-1/EBL mosaic whose tandem AMA-1-like domains, not Duffy-binding-like domains, mediate erythrocyte binding.\",\n      \"evidence\": \"In vitro erythrocyte-binding of recombinant M1/M2 domains expressed in COS cells with sequence/domain analysis and IFA, in P. yoelii and P. berghei orthologues\",\n      \"pmids\": [\"9448314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Native receptor on the erythrocyte not identified\", \"Binding of full-length native protein versus isolated domains not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii yoelii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Co-localization with rhoptry markers and timing of appearance placed MAEBL in the merozoite apical secretory machinery, distinguishing it biochemically from soluble DBL-EBP adhesins.\",\n      \"evidence\": \"IFA co-localization with AMA-1 and 235 kDa rhoptry proteins, immunoprecipitation and Western blot in P. yoelii YM\",\n      \"pmids\": [\"9851604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in the rhoptry not tested\", \"Basis of the ~120/128 kDa doublet not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"YM\"}]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Tracing MAEBL through ER, Golgi, and rhoptry precursors defined its trafficking route to the apical organelles during schizogony.\",\n      \"evidence\": \"Live and fixed IFA with ER and Golgi markers across schizont differentiation in P. yoelii\",\n      \"pmids\": [\"10838220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking signals/sorting determinants not mapped\", \"Single-species observation\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout in P. berghei answered which life-cycle step requires MAEBL, showing it is essential for sporozoite invasion of the mosquito salivary gland but dispensable for motility and vertebrate infectivity as assayed.\",\n      \"evidence\": \"Targeted gene disruption with salivary gland invasion and motility assays plus microneme IFA in P. berghei\",\n      \"pmids\": [\"12021311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Salivary gland receptor for MAEBL unknown\", \"Mechanistic step of attachment versus invasion not separated\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Reciprocal co-localization and fractionation in P. falciparum showed MAEBL associates with rhoptry (not microneme) proteins in merozoites and is processed so ligand domains are shed while the membrane-proximal domain is retained.\",\n      \"evidence\": \"IFA co-localization with RhopH2/RAP-1 versus EBA-175/BAEBL and Western blot of supernatant versus detergent fractions in P. falciparum\",\n      \"pmids\": [\"12076768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease responsible for ectodomain shedding not identified here\", \"Functional consequence of shedding untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Enzymatic dissection of M2-domain binding defined the receptor as protease-sensitive and sialic-acid-independent, refining the biochemical nature of MAEBL-erythrocyte engagement.\",\n      \"evidence\": \"Recombinant PfM2 erythrocyte-binding assay with papain/neuraminidase treatments plus IFA in P. falciparum\",\n      \"pmids\": [\"12165387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the receptor not determined\", \"Only M2 tested for receptor properties\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Stage-resolved imaging showed MAEBL redistributes from storage organelles to the sporozoite surface as oocysts mature, linking its relocation to acquisition of salivary-gland invasiveness.\",\n      \"evidence\": \"IFA at defined oocyst developmental time-points in P. berghei\",\n      \"pmids\": [\"14627711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for redistribution unknown\", \"Correlative rather than causal link to invasion\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Isoform mapping revealed that salivary gland sporozoites uniquely express a full-length membrane form retaining both M1 and M2 domains, and antibodies to these domains block sporozoite development, implicating the ligand domains functionally.\",\n      \"evidence\": \"Stage-specific Western blots and antibody inhibition of exoerythrocytic development in P. berghei\",\n      \"pmids\": [\"15155670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target of the inhibitory antisera in the invasion pathway not defined\", \"Whether M1 and M2 have distinct functions unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Peptide scanning localized erythrocyte-binding activity to discrete high-activity regions across M1, M2, and the repeat region and tied binding to a 33 kDa red-cell membrane protein.\",\n      \"evidence\": \"Synthetic peptide binding assays, merozoite invasion inhibition, and RBC membrane protein binding in P. falciparum\",\n      \"pmids\": [\"14766210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"33 kDa RBC protein not identified\", \"Peptide-level binding may not reflect native domain architecture\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery of conserved, developmentally controlled alternative splicing showed the maebl locus can produce either the type I membrane protein or a predicted soluble isoform, providing a regulatory switch over MAEBL form.\",\n      \"evidence\": \"RT-PCR, Western blot, and splice-variant sequence analysis across P. falciparum, P. berghei, and P. yoelii\",\n      \"pmids\": [\"15465047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulators of splice-site choice unknown\", \"Function of the soluble isoform not directly tested here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Knockout in P. falciparum established that blood-stage MAEBL is not required for erythrocytic growth in vitro, narrowing its essential roles to other stages.\",\n      \"evidence\": \"Targeted gene disruption in P. falciparum (abstract-level)\",\n      \"pmids\": [\"15811533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract only, limited methodological detail\", \"Possible redundancy with other invasion ligands not examined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying MAEBL as a selective PfROM4 substrate provided a molecular mechanism for membrane release/processing, dependent on the MAEBL transmembrane domain.\",\n      \"evidence\": \"Heterologous rhomboid cleavage assay with transmembrane-domain swaps in P. falciparum\",\n      \"pmids\": [\"17040128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo timing and requirement of PfROM4 cleavage of MAEBL not shown\", \"Functional consequence of cleavage for invasion untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Isoform-specific allelic replacement demonstrated that only the transmembrane MAEBL isoform supports salivary gland invasion, assigning function to a specific molecular form.\",\n      \"evidence\": \"Knockout and single-isoform allelic replacement with salivary gland invasion assays in P. falciparum NF54\",\n      \"pmids\": [\"18509478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role, if any, of the soluble isoform not defined\", \"Molecular partner engaged by the transmembrane form unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the maebl mRNA revealed a bicistronic architecture with a >2 kb 5'-UTR containing an upstream ORF and an upstream minimal promoter, defining an unusual transcriptional/translational control layer.\",\n      \"evidence\": \"Northern blot, RT-PCR, 5'-RACE, and transient CAT reporter assays in P. falciparum\",\n      \"pmids\": [\"18950624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory function of the upstream ORF not established\", \"Translational control mechanism not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knockout with complementation in P. falciparum uncovered a distinct essential role for MAEBL in sporozoite cell traversal and hepatocyte invasion, extending its function beyond salivary gland entry into liver-stage infection.\",\n      \"evidence\": \"Gene knockout with genetic complementation, cell traversal and hepatocyte invasion assays, and humanized chimeric liver mouse infection in P. falciparum\",\n      \"pmids\": [\"28371168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hepatocyte receptor/ligand for MAEBL not identified\", \"Mechanistic distinction between traversal and productive invasion not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Knockout/complementation in P. berghei consolidated MAEBL's role in hepatocyte adhesion, gliding motility, wounding, and invasion, and showed stage-dependent surface/microneme localization with declining levels after salivary gland entry.\",\n      \"evidence\": \"Transgenic knockout and complemented parasites, live mouse imaging, hepatocyte adhesion/invasion, gliding and wounding assays, and myc-tagged MAEBL IFA in P. berghei\",\n      \"pmids\": [\"35628522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of adhesion to hepatocytes unknown\", \"Cause of post-salivary-gland decline in MAEBL not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identities of the MAEBL receptors on erythrocytes, mosquito salivary glands, and hepatocytes, and the in vivo role of PfROM4 cleavage, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No host receptor for any MAEBL-dependent invasion step has been molecularly identified\", \"In vivo functional requirement and timing of PfROM4 processing of MAEBL untested\", \"Function of the soluble spliced isoform undefined\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0050839\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0008233\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020008\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [3, 6, 15]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [1, 4, 6, 15]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [3, 12, 14, 15]},\n      {\"term_id\": \"GO:0006909\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0006886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0000380\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfROM4 (rhomboid intramembrane protease that cleaves MAEBL; PfROM1 does not) [#11]\"\n    ],\n    \"other_free_text\": [\n      \"Chimeric domain architecture: N-terminal cysteine-rich AMA-1-like domains (tandem M1 and M2), plus a C-terminal EBL-family-homologous region [#0].\",\n      \"M2 domain binds a papain-sensitive, sialic-acid-independent erythrocyte receptor; high-activity binding peptides span M1, M2, and the repeat region and engage a 33 kDa RBC membrane protein [#5, #8].\",\n      \"Merozoite MAEBL is processed so amino ligand domains are shed while the transmembrane-proximal carboxyl domain is retained in detergent fractions [#4].\",\n      \"Only the transmembrane isoform supports mosquito salivary gland invasion; a predicted soluble isoform is generated by conserved developmentally controlled alternative splicing [#9, #12].\",\n      \"maebl is encoded on a bicistronic mRNA with a >2 kb 5'-UTR containing an upstream small ORF (PF11_0485) and the minimal promoter [#13].\",\n      \"Blood-stage MAEBL is dispensable for erythrocytic growth in vitro; sporozoite roles in salivary gland invasion, cell traversal, and hepatocyte invasion are essential and complementable [#10, #12, #14, #15].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1147800","name":null,"product":"membrane associated erythrocyte binding-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0901300","name":null,"product":"membrane associated erythrocyte binding-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0945700","name":null,"product":"membrane associated erythrocyte binding-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"MAEBL","evaluation":null}