{"gene":"PF3D7_0102200","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":1985,"finding":"RESA is localized within dense vesicles presumed to be micronemes in merozoites, and is present at the membrane of erythrocytes infected with ring-stage parasites. Within merozoites, RESA is largely Triton X-100 soluble, but becomes Triton X-100 insoluble upon association with the erythrocyte membrane.","method":"Immunoelectron microscopy with protein A gold; Triton X-100 fractionation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunoelectron microscopy localization with biochemical fractionation, foundational localization study replicated by subsequent work","pmids":["3894564"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1990,"finding":"RESA is localized in dense granules of P. falciparum merozoites (not micronemes as previously suggested), as demonstrated by immunoelectron microscopy.","method":"Immunoelectron microscopy","journal":"Experimental parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunoelectron microscopy, corrected earlier microneme assignment, independently replicated by Culvenor et al. 1991","pmids":["2209790"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"finding":"RESA is released from merozoite dense granules after erythrocyte invasion (not via apical rhoptry ducts at the time of merozoite attachment). Post-invasion, RESA labeling was found in pockets of the parasitophorous vacuole space or in aggregates closely associated with the parasitophorous vacuole.","method":"Postembedding immunolabeling electron microscopy of newly invaded erythrocytes","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct electron microscopy of invasion time course, consistent with Aikawa et al. 1990, establishes secretion route","pmids":["1997422"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"finding":"RESA associates with the Triton X-100-insoluble inner face of the host erythrocyte membrane skeleton. RESA co-sediments with the actin-spectrin-band 4.1 ternary complex and co-precipitates with spectrin using anti-spectrin antibodies. Excess purified spectrin reduces RESA association with the membrane, indicating spectrin is the binding partner.","method":"In vitro binding assay with spent culture supernatants; co-sedimentation; co-immunoprecipitation with anti-spectrin antibodies; competition with purified spectrin","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus competition assay, multiple orthogonal methods in one study, replicated by subsequent work","pmids":["1852169"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"finding":"RESA is localized to the cytoplasmic face of the erythrocyte membrane (not the outer surface). RESA from spent culture medium binds inside-out vesicles (IOVs) and cytoskeletal shells but not sealed right-side-out vesicles. Spectrin depletion from IOVs abolishes RESA binding, indicating spectrin mediates the association.","method":"Surface radioiodination; immunofluorescence of surface-modified cells and IOVs; spectrin-depletion binding assay","journal":"Experimental parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (radioiodination, IFA, spectrin depletion), consistent with Foley et al. 1991","pmids":["2055301"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1990,"finding":"RESA is phosphorylated on serine (and minor threonine) residues specifically when it becomes associated with the erythrocyte membrane skeleton, not while in mature parasites. Phosphorylation is carried out by an erythrocyte membrane kinase, not a parasite-encoded enzyme. Soluble RESA from culture supernatants, when bound to IOVs from normal uninfected erythrocytes, is also phosphorylated by the erythrocyte kinase.","method":"[gamma-32P]ATP labeling of IOVs; immunoprecipitation; phosphoamino acid analysis; [32P]phosphate labeling of intact parasitized erythrocytes; synchronized parasite labeling","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with immunoprecipitation and phosphoamino acid analysis, single lab but multiple orthogonal methods","pmids":["2108327"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"The membrane-binding domain of RESA was mapped to a 48-amino-acid region located between the two blocks of repetitive sequence. The tandem repeats are not required for membrane association. Large N-terminal deletions do not affect binding. This binding domain does not overlap the region sharing homology with the E. coli chaperone DnaJ.","method":"Deletion mutagenesis of recombinant RESA fragments expressed in E. coli; in vitro binding assay with IOVs","journal":"Experimental parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — deletion mutagenesis combined with in vitro binding assay, single lab but systematic domain mapping","pmids":["7957755"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"A recombinant RESA fragment binds to IOVs in an apparently saturable manner and remains associated with the erythrocyte cytoskeleton after Triton X-100 extraction. Recombinant RESA partially protects spectrin against heat-induced conformational changes in vitro (fluorescence polarization). Erythrocytes infected with a RESA-negative strain (FCR3) are more susceptible to heat-induced fragmentation than RESA-positive infected erythrocytes. However, resealing erythrocytes with anti-RESA antibodies did not block invasion, indicating RESA is not essential for the invasion process per se.","method":"In vitro binding assay; Triton X-100 fractionation; steady-state fluorescence polarization of fluorescein-labeled spectrin; heat-induced fragmentation assay of RESA(+) vs RESA(-) infected erythrocytes; erythrocyte resealing with antibodies","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in vitro plus isogenic strain comparison, multiple orthogonal methods in one study","pmids":["7984188"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"RESA binds to a 108-amino-acid fragment of beta-spectrin (residues 663-770 of RESA bind repeat 16 of the beta-chain, close to the labile dimer-dimer self-association site). This RESA fragment stabilizes spectrin tetramers against dissociation into dimers both in situ and in solution. Erythrocytes resealed to contain the RESA(663-770) fragment display resistance to invasion by P. falciparum merozoites, suggesting RESA prevents reinvasion of already-parasitized cells.","method":"In vitro binding assay with defined spectrin fragments; spectrin tetramer stabilization assay in solution and in situ; erythrocyte resealing with RESA fragment followed by invasion assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in vitro with defined peptide fragments, tetramer stabilization assay, functional invasion assay; single lab but multiple orthogonal methods","pmids":["17468340"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"RESA plays a major role in reducing deformability of host RBCs at the early ring stage of parasite development, but not at more advanced stages. The effect of RESA on deformability is more pronounced at febrile temperature (41°C) than at normal body temperature. This was established using parental, RESA gene-disrupted, and revertant isogenic clones measured by optical tweezers.","method":"Optical tweezers measurement of RBC mechanical properties; targeted gene disruption with isogenic parental and revertant clones; comparison at physiological and febrile temperatures","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean gene KO with isogenic revertant controls plus quantitative biophysical assay (optical tweezers), multiple temperature conditions","pmids":["17517609"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Gene disruption of resa1 confirmed RESA's critical role in the surface reactivity of immune adult sera on glutaraldehyde-fixed ring stages. Absence of RESA did not influence merozoite invasion or erythrocyte membrane rigidity under basal conditions, but resa1-KO parasites showed marked susceptibility to heat shock: heat-induced vesiculation occurred in resa1-KO infected erythrocytes (similar to uninfected erythrocytes), whereas parental and resa3-KO infected erythrocytes were protected. A 6-hour exposure at 41°C caused 33% culture inhibition in resa1-KO but not parental or resa3-KO parasites. Absence of RESA was associated with a modest increase in cytoadhesion to CD36 under flow. RESA did not modulate virulence in Saimiri sciureus.","method":"Targeted gene disruption (resa1-KO) with isogenic parental and resa3-KO controls; heat shock assay; invasion assay; membrane rigidity assay; flow-based CD36 cytoadhesion assay; Saimiri sciureus infection model","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic gene KO with multiple phenotypic readouts and parallel resa3-KO controls, multiple orthogonal methods","pmids":["15853885"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"RESA influences the dynamic microcirculatory behavior of ring-stage P. falciparum-infected RBCs. RESA-expressing Pf-RBCs showed decreased membrane fluctuations (diffraction phase microscopy), reduced transit velocity in microfluidic experiments, and impaired traversal in microsphere filtration at febrile temperature. These effects were RESA-dependent and fever-enhanced.","method":"Diffraction phase microscopy; microfluidic transit assay; microsphere filtration; comparison of RESA-expressing vs. RESA-disrupted isogenic parasite lines","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isogenic RESA-KO comparison using multiple biophysical assays (diffraction phase microscopy, microfluidics, filtration), single lab","pmids":["22937223"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"Trafficking of RESA to the host erythrocyte cytosol requires both an appropriate N-terminal transport signal (hydrophobic stretch acting as a non-canonical secretory signal) AND correct timing of expression (schizont stage under the RESA promoter). Expression of RESA-GFP under a trophozoite-specific promoter mistargeted the chimeric protein to the parasitophorous vacuole, whereas expression under the native RESA promoter in schizont stages enabled correct trafficking to the host erythrocyte.","method":"Transfection of P. falciparum with RESA-GFP chimeric constructs under different promoters; fluorescence microscopy; stage-specific expression analysis","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging of trafficking with promoter-swap experiment defining two requirements, single lab but clean functional consequence","pmids":["15385514"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"An extended PRESAN domain (comprising the PRESAN domain and preceding sequence) of PHISTb proteins is sufficient to localize proteins to the erythrocyte periphery and functions as a cytoskeleton-binding domain. This domain was validated in RESA, identifying a second cytoskeleton-binding domain that functions independently of RESA's known spectrin-binding domain.","method":"Subcellular localization of truncated/chimeric constructs by microscopy; Triton X-100 fractionation for cytoskeletal association; domain deletion and swap experiments validated in RESA","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization with functional domain validation in RESA, single lab, single method set","pmids":["25106850"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"Loss of RESA (in parasites with a large chromosome 1 deletion) significantly affects the ability of parasitized RBCs to adhere under flow conditions to CD36, as measured by a competitive flow-based adhesion assay.","method":"Flow-based cytoadhesion assay using parasite lines lacking specific proteins including RESA","journal":"British journal of haematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single adhesion assay, RESA loss achieved via large chromosomal deletion (not targeted KO), potentially confounded by loss of other genes on the deletion","pmids":["11918556"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1986,"finding":"The RESA gene consists of two exons with a short intron near the 5' end of the coding region. A hydrophobic amino acid segment encoded by the 3' end of exon 1 is consistent with a trafficking signal sequence. Restriction fragment length polymorphisms define two different alleles represented by isolates FC27 and NF7.","method":"Nucleotide sequencing; gene structure analysis; RFLP analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete gene sequencing with structural analysis, foundational gene structure study","pmids":["3537955"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1989,"finding":"Expression of RESA is prevented in the P. falciparum isolate FCR3 because the 5' end of the RESA gene has been inverted and partly deleted, with a telomere added to it. This represents a subtelomeric deletion mechanism silencing the gene.","method":"Southern blotting; molecular cloning; sequence analysis of the FCR3 RESA locus","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct molecular characterization of gene structure alteration explaining lack of expression, single lab","pmids":["2677678"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"FCR3"}]},{"year":2019,"finding":"RESA, as a representative exported protein, failed to be transported across the parasitophorous vacuolar membrane to the host erythrocyte in parasites in which the rhoptry protein RON3 was conditionally disrupted, demonstrating that RON3 is required for functional PTEX-mediated export of RESA.","method":"Conditional disruption of RON3; immunofluorescence assay monitoring RESA localization in RON3-deficient parasites","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean conditional KO with direct localization readout for RESA export, single lab, single method for RESA-specific finding","pmids":["31289187"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"A crystal structure of two Fab domains of human monoclonal antibody B1E11K in complex with RESA showed binding to a repeating epitope motif in a head-to-head conformation involving affinity-matured homotypic interactions between the two Fab domains.","method":"X-ray crystallography of Fab-RESA complex; human monoclonal antibody isolation by single B cell activation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation of binding mode, single lab but rigorous structural method","pmids":["39817720"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Ultrastructural expansion microscopy (U-ExM) confirmed RESA localization in dense granules of P. falciparum 3D7 merozoites and demonstrated translocation of RESA to the infected erythrocyte membrane in early ring-stage parasites, consistent with immunoelectron microscopy data.","method":"Ultrastructural expansion microscopy (U-ExM) with anti-RESA mAb and NHS-ester protein staining","journal":"Parasitology international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by novel expansion microscopy method consistent with established IEM data, single lab","pmids":["39732432"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"finding":"Using RESA localization as a proxy marker for dense granule formation, dense granule biogenesis commences approximately 37 minutes prior to schizont egress.","method":"Time-lapse fluorescence microscopy of RESA-expressing parasites to track DG formation timing","journal":"Microbiology (Reading, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct live-cell imaging using RESA as DG marker, single lab, RESA used as proxy rather than primary subject","pmids":["37647112"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"RESA (PF3D7_0102200) is a ~155 kDa protein stored in merozoite dense granules that is released into the parasitophorous vacuole after erythrocyte invasion (not before), traffics to the inner face of the host erythrocyte membrane in a process requiring both its N-terminal hydrophobic signal sequence and schizont-stage expression timing, where it binds to repeat 16 of beta-spectrin via a defined 108-amino-acid domain (residues 663-770) as well as through an independent PRESAN-domain interaction, stabilizes spectrin tetramers against dissociation, reduces ring-stage RBC deformability and microcirculatory transit especially at febrile temperatures, protects the erythrocyte cytoskeleton from heat-induced damage, suppresses reinvasion of already-parasitized cells, and is phosphorylated on serine/threonine by an erythrocyte membrane kinase upon membrane association."},"narrative":{"mechanistic_narrative":"RESA (PF3D7_0102200) is a Plasmodium falciparum ring-stage antigen that remodels the host erythrocyte cytoskeleton to alter the mechanical and thermal stability of infected red cells [PMID:1852169, PMID:17517609]. Encoded by a two-exon gene whose 3' end of exon 1 specifies a hydrophobic trafficking signal [PMID:3537955], RESA is synthesized during the schizont stage and stored in merozoite dense granules [PMID:2209790, PMID:39732432], from which it is discharged into the parasitophorous vacuole space only after erythrocyte invasion rather than at merozoite attachment [PMID:1997422]. Correct delivery to the host erythrocyte cytosol requires both this N-terminal transport signal and schizont-stage expression timing [PMID:15385514], and export across the parasitophorous vacuolar membrane depends on functional PTEX-mediated transport gated by the rhoptry protein RON3 [PMID:31289187]. At the cytoplasmic face of the erythrocyte membrane skeleton [PMID:2055301], RESA becomes Triton X-100-insoluble and binds spectrin, co-sedimenting with the actin-spectrin-band 4.1 complex and co-precipitating with spectrin [PMID:1852169]; it engages repeat 16 of beta-spectrin through residues 663-770 near the labile dimer-dimer self-association site, and stabilizes spectrin tetramers against dissociation [PMID:17468340]. A second, independent cytoskeleton-binding activity resides in an extended PRESAN domain [PMID:25106850], while an internal 48-amino-acid segment between the two repeat blocks mediates membrane association independently of the tandem repeats [PMID:7957755]. Upon membrane association RESA is phosphorylated on serine and minor threonine residues by an erythrocyte membrane kinase rather than a parasite enzyme [PMID:2108327]. Functionally, isogenic gene-disruption studies show RESA reduces ring-stage RBC deformability and microcirculatory transit, effects that are enhanced at febrile temperature [PMID:17517609, PMID:22937223], and protects the infected-cell cytoskeleton against heat-induced vesiculation and fragmentation [PMID:7984188, PMID:15853885]; RESA is not required for merozoite invasion, but erythrocytes pre-loaded with the spectrin-binding fragment resist reinvasion [PMID:17468340, PMID:15853885].","teleology":[{"year":1985,"claim":"Establishing where RESA resides in the merozoite and infected cell was the first step in defining its stage of action, showing it is a stored protein that relocates to the erythrocyte membrane upon invasion.","evidence":"Immunoelectron microscopy with protein A gold plus Triton X-100 fractionation in P. falciparum","pmids":["3894564"],"confidence":"High","gaps":["Precise granule identity (microneme vs dense granule) unresolved at this stage","Mechanism of membrane insolubility transition undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1986,"claim":"Determining the gene structure identified a hydrophobic exon 1 segment consistent with a trafficking signal and revealed allelic polymorphism, framing how RESA reaches the erythrocyte.","evidence":"Nucleotide sequencing, gene structure analysis, and RFLP analysis in P. falciparum","pmids":["3537955"],"confidence":"High","gaps":["Signal function not experimentally tested here","Functional significance of allelic variation unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1989,"claim":"Explaining why isolate FCR3 lacks RESA showed the locus is silenced by subtelomeric inversion/deletion, providing a natural RESA-negative background for functional comparison.","evidence":"Southern blotting, cloning, and sequence analysis of the FCR3 RESA locus","pmids":["2677678"],"confidence":"High","gaps":["Does not address RESA's normal function","Other genes potentially affected by the chromosomal rearrangement not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":"FCR3"}]},{"year":1990,"claim":"Refining the granule assignment corrected the earlier microneme localization, placing RESA specifically in dense granules and clarifying its secretion compartment.","evidence":"Immunoelectron microscopy in P. falciparum","pmids":["2209790"],"confidence":"High","gaps":["Timing and route of granule discharge not yet established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1990,"claim":"Asking whether RESA is modified after export revealed it is phosphorylated by a host erythrocyte kinase specifically on membrane association, distinguishing a host-driven post-translational event from parasite enzymology.","evidence":"[gamma-32P]ATP labeling of IOVs, immunoprecipitation, phosphoamino acid analysis, and labeling of synchronized parasites in P. falciparum","pmids":["2108327"],"confidence":"High","gaps":["Identity of the erythrocyte kinase unknown","Functional consequence of phosphorylation undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"claim":"Defining the secretion route showed RESA is released from dense granules into the parasitophorous vacuole after invasion, not through rhoptry ducts at attachment, ordering its delivery relative to invasion.","evidence":"Postembedding immunolabeling electron microscopy of newly invaded erythrocytes in P. falciparum","pmids":["1997422"],"confidence":"High","gaps":["Molecular machinery of vacuolar-to-cytosol transfer not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"claim":"Identifying the binding partner and topology established that RESA sits on the cytoplasmic face of the membrane skeleton and associates with spectrin, pinpointing its molecular target.","evidence":"Co-sedimentation with the actin-spectrin-band 4.1 complex, reciprocal co-IP with anti-spectrin, spectrin competition, IOV binding, and spectrin-depletion assays in P. falciparum","pmids":["1852169","2055301"],"confidence":"High","gaps":["Binding region on RESA not yet mapped","Physiological consequence of spectrin binding not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"claim":"Dissecting RESA's domains localized membrane binding to a 48-residue segment between the repeat blocks and demonstrated that recombinant RESA protects spectrin from heat-induced changes, linking binding to cytoskeletal stabilization.","evidence":"Deletion mutagenesis with IOV binding assays, fluorescence polarization of labeled spectrin, and heat-fragmentation comparison of RESA(+) vs RESA(-) infected cells in P. falciparum","pmids":["7957755","7984188"],"confidence":"High","gaps":["Precise spectrin residues contacted not yet defined","RESA shown non-essential for invasion but reinvasion effect not yet tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"claim":"Determining what governs export showed both the N-terminal hydrophobic signal and schizont-stage expression timing are required, since a trophozoite promoter mistargeted RESA-GFP to the vacuole.","evidence":"Transfection with RESA-GFP chimeras under different promoters and fluorescence microscopy in P. falciparum","pmids":["15385514"],"confidence":"High","gaps":["Molecular recognition of the signal by the export machinery not defined here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"A targeted resa1 knockout with isogenic controls delivered the loss-of-function test, showing RESA is dispensable for invasion and basal rigidity but is required to protect infected cells against heat shock.","evidence":"resa1-KO with parental and resa3-KO controls, heat shock, invasion, rigidity, CD36 flow adhesion, and Saimiri infection assays in P. falciparum","pmids":["15853885"],"confidence":"High","gaps":["Mechanism connecting spectrin stabilization to heat protection at cellular scale not fully resolved","Modest CD36 adhesion effect not mechanistically explained"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"Mapping RESA to beta-spectrin repeat 16 and demonstrating tetramer stabilization plus reinvasion resistance connected the molecular interaction to both mechanical stabilization and a barrier against superinfection.","evidence":"Defined spectrin-fragment binding, tetramer stabilization assays, resealed-fragment invasion assays, and optical-tweezers deformability with isogenic KO/revertant clones in P. falciparum","pmids":["17468340","17517609"],"confidence":"High","gaps":["Structural basis of the RESA-spectrin contact not determined","Relationship between deformability reduction and in vivo sequestration not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Extending the phenotype to microcirculatory behavior showed RESA reduces membrane fluctuations and transit and impairs traversal at febrile temperature, tying its cytoskeletal action to physiological blood flow.","evidence":"Diffraction phase microscopy, microfluidic transit, and microsphere filtration comparing isogenic RESA-expressing vs disrupted lines in P. falciparum","pmids":["22937223"],"confidence":"High","gaps":["In vivo consequences for sequestration/pathogenesis not directly measured"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Identifying an extended PRESAN cytoskeleton-binding domain revealed a second, spectrin-binding-independent membrane-anchoring activity in RESA.","evidence":"Localization of truncated/chimeric constructs, Triton X-100 fractionation, and domain swaps validated in RESA in P. falciparum","pmids":["25106850"],"confidence":"Medium","gaps":["Cytoskeletal ligand of the PRESAN domain not identified","Single lab, single method set"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Testing export dependency showed RESA fails to reach the host erythrocyte when the rhoptry protein RON3 is conditionally disrupted, placing RESA export downstream of RON3-gated PTEX function.","evidence":"Conditional RON3 disruption with immunofluorescence tracking of RESA localization in P. falciparum","pmids":["31289187"],"confidence":"Medium","gaps":["Direct interaction of RESA with PTEX components not shown","Single method for the RESA-specific readout"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Independent expansion microscopy re-confirmed dense-granule storage and ring-stage translocation of RESA to the erythrocyte membrane, corroborating decades-old immuno-EM with a modern method.","evidence":"Ultrastructural expansion microscopy with anti-RESA mAb in P. falciparum 3D7","pmids":["39732432"],"confidence":"Medium","gaps":["No new mechanistic information beyond localization confirmation"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2025,"claim":"A crystal structure of the human antibody B1E11K bound to RESA's repeating epitope defined the immune-recognition mode via homotypic Fab-Fab interactions, characterizing RESA as an antigenic target.","evidence":"X-ray crystallography of a Fab-RESA complex with antibody from single B cell activation in P. falciparum","pmids":["39817720"],"confidence":"High","gaps":["Structure covers a repeat epitope, not the spectrin-binding or PRESAN domains","Protective significance of the antibody not established here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How the two independent cytoskeleton-binding activities (the 663-770 beta-spectrin site and the PRESAN domain) and host-kinase phosphorylation are integrated into RESA's mechanical and heat-protective effects, and whether these translate to in vivo pathogenesis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the RESA-spectrin interface","Functional role of phosphorylation untested","Relative contribution of spectrin-binding vs PRESAN domain to cellular phenotypes unquantified","In vivo sequestration/virulence consequences not directly demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["spectrin-actin-band 4.1 erythrocyte membrane skeleton (co-sedimentation) [#3]"],"partners":["BETA-SPECTRIN (REPEAT 16; RESA RESIDUES 663-770) [#3, #8]","ERYTHROCYTE MEMBRANE SERINE/THREONINE KINASE (PHOSPHORYLATES RESA) [#5]","RON3 (REQUIRED FOR PTEX-MEDIATED EXPORT OF RESA) [#17]","HUMAN MONOCLONAL ANTIBODY B1E11K (BINDS RESA REPEAT EPITOPE) [#18]"],"other_free_text":["Stored in merozoite dense granules and discharged into the parasitophorous vacuole after invasion, not before [#1, #2]","Two-exon gene; hydrophobic exon 1 segment acts as a non-canonical trafficking signal; correct export requires this signal plus schizont-stage timing [#12, #15]","48-amino-acid membrane-binding domain between the repeat blocks; tandem repeats and large N-terminal deletions not required for binding [#6]","Reduces ring-stage RBC deformability and microcirculatory transit, effects enhanced at febrile temperature [#9, #11]","Protects infected-cell cytoskeleton from heat-induced vesiculation/fragmentation [#7, #10]","Dispensable for merozoite invasion; spectrin-binding fragment confers resistance to reinvasion [#7, #8, #10]","Silenced in isolate FCR3 by subtelomeric inversion/deletion [#16]","Modest effect on CD36 cytoadhesion under flow [#10, #14]","Used as a dense-granule biogenesis marker (~37 min before egress) [#20]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"11920300","id":"PMC_11920300","title":"A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea.","date":"2002","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/11920300","citation_count":404,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ring-infected erythrocyte surface antigen"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"6382025","id":"PMC_6382025","title":"Immune sera recognize on erythrocytes Plasmodium falciparum antigen composed of repeated amino acid 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Within merozoites, RESA is largely Triton X-100 soluble, but becomes Triton X-100 insoluble upon association with the erythrocyte membrane.\",\n      \"method\": \"Immunoelectron microscopy with protein A gold; Triton X-100 fractionation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct immunoelectron microscopy localization with biochemical fractionation, foundational localization study replicated by subsequent work\",\n      \"pmids\": [\"3894564\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"RESA is localized in dense granules of P. falciparum merozoites (not micronemes as previously suggested), as demonstrated by immunoelectron microscopy.\",\n      \"method\": \"Immunoelectron microscopy\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct immunoelectron microscopy, corrected earlier microneme assignment, independently replicated by Culvenor et al. 1991\",\n      \"pmids\": [\"2209790\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"RESA is released from merozoite dense granules after erythrocyte invasion (not via apical rhoptry ducts at the time of merozoite attachment). Post-invasion, RESA labeling was found in pockets of the parasitophorous vacuole space or in aggregates closely associated with the parasitophorous vacuole.\",\n      \"method\": \"Postembedding immunolabeling electron microscopy of newly invaded erythrocytes\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct electron microscopy of invasion time course, consistent with Aikawa et al. 1990, establishes secretion route\",\n      \"pmids\": [\"1997422\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"RESA associates with the Triton X-100-insoluble inner face of the host erythrocyte membrane skeleton. RESA co-sediments with the actin-spectrin-band 4.1 ternary complex and co-precipitates with spectrin using anti-spectrin antibodies. Excess purified spectrin reduces RESA association with the membrane, indicating spectrin is the binding partner.\",\n      \"method\": \"In vitro binding assay with spent culture supernatants; co-sedimentation; co-immunoprecipitation with anti-spectrin antibodies; competition with purified spectrin\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus competition assay, multiple orthogonal methods in one study, replicated by subsequent work\",\n      \"pmids\": [\"1852169\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"RESA is localized to the cytoplasmic face of the erythrocyte membrane (not the outer surface). RESA from spent culture medium binds inside-out vesicles (IOVs) and cytoskeletal shells but not sealed right-side-out vesicles. Spectrin depletion from IOVs abolishes RESA binding, indicating spectrin mediates the association.\",\n      \"method\": \"Surface radioiodination; immunofluorescence of surface-modified cells and IOVs; spectrin-depletion binding assay\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (radioiodination, IFA, spectrin depletion), consistent with Foley et al. 1991\",\n      \"pmids\": [\"2055301\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"RESA is phosphorylated on serine (and minor threonine) residues specifically when it becomes associated with the erythrocyte membrane skeleton, not while in mature parasites. Phosphorylation is carried out by an erythrocyte membrane kinase, not a parasite-encoded enzyme. Soluble RESA from culture supernatants, when bound to IOVs from normal uninfected erythrocytes, is also phosphorylated by the erythrocyte kinase.\",\n      \"method\": \"[gamma-32P]ATP labeling of IOVs; immunoprecipitation; phosphoamino acid analysis; [32P]phosphate labeling of intact parasitized erythrocytes; synchronized parasite labeling\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with immunoprecipitation and phosphoamino acid analysis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"2108327\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The membrane-binding domain of RESA was mapped to a 48-amino-acid region located between the two blocks of repetitive sequence. The tandem repeats are not required for membrane association. Large N-terminal deletions do not affect binding. This binding domain does not overlap the region sharing homology with the E. coli chaperone DnaJ.\",\n      \"method\": \"Deletion mutagenesis of recombinant RESA fragments expressed in E. coli; in vitro binding assay with IOVs\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — deletion mutagenesis combined with in vitro binding assay, single lab but systematic domain mapping\",\n      \"pmids\": [\"7957755\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A recombinant RESA fragment binds to IOVs in an apparently saturable manner and remains associated with the erythrocyte cytoskeleton after Triton X-100 extraction. Recombinant RESA partially protects spectrin against heat-induced conformational changes in vitro (fluorescence polarization). Erythrocytes infected with a RESA-negative strain (FCR3) are more susceptible to heat-induced fragmentation than RESA-positive infected erythrocytes. However, resealing erythrocytes with anti-RESA antibodies did not block invasion, indicating RESA is not essential for the invasion process per se.\",\n      \"method\": \"In vitro binding assay; Triton X-100 fractionation; steady-state fluorescence polarization of fluorescein-labeled spectrin; heat-induced fragmentation assay of RESA(+) vs RESA(-) infected erythrocytes; erythrocyte resealing with antibodies\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in vitro plus isogenic strain comparison, multiple orthogonal methods in one study\",\n      \"pmids\": [\"7984188\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RESA binds to a 108-amino-acid fragment of beta-spectrin (residues 663-770 of RESA bind repeat 16 of the beta-chain, close to the labile dimer-dimer self-association site). This RESA fragment stabilizes spectrin tetramers against dissociation into dimers both in situ and in solution. Erythrocytes resealed to contain the RESA(663-770) fragment display resistance to invasion by P. falciparum merozoites, suggesting RESA prevents reinvasion of already-parasitized cells.\",\n      \"method\": \"In vitro binding assay with defined spectrin fragments; spectrin tetramer stabilization assay in solution and in situ; erythrocyte resealing with RESA fragment followed by invasion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in vitro with defined peptide fragments, tetramer stabilization assay, functional invasion assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17468340\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RESA plays a major role in reducing deformability of host RBCs at the early ring stage of parasite development, but not at more advanced stages. The effect of RESA on deformability is more pronounced at febrile temperature (41°C) than at normal body temperature. This was established using parental, RESA gene-disrupted, and revertant isogenic clones measured by optical tweezers.\",\n      \"method\": \"Optical tweezers measurement of RBC mechanical properties; targeted gene disruption with isogenic parental and revertant clones; comparison at physiological and febrile temperatures\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean gene KO with isogenic revertant controls plus quantitative biophysical assay (optical tweezers), multiple temperature conditions\",\n      \"pmids\": [\"17517609\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Gene disruption of resa1 confirmed RESA's critical role in the surface reactivity of immune adult sera on glutaraldehyde-fixed ring stages. Absence of RESA did not influence merozoite invasion or erythrocyte membrane rigidity under basal conditions, but resa1-KO parasites showed marked susceptibility to heat shock: heat-induced vesiculation occurred in resa1-KO infected erythrocytes (similar to uninfected erythrocytes), whereas parental and resa3-KO infected erythrocytes were protected. A 6-hour exposure at 41°C caused 33% culture inhibition in resa1-KO but not parental or resa3-KO parasites. Absence of RESA was associated with a modest increase in cytoadhesion to CD36 under flow. RESA did not modulate virulence in Saimiri sciureus.\",\n      \"method\": \"Targeted gene disruption (resa1-KO) with isogenic parental and resa3-KO controls; heat shock assay; invasion assay; membrane rigidity assay; flow-based CD36 cytoadhesion assay; Saimiri sciureus infection model\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic gene KO with multiple phenotypic readouts and parallel resa3-KO controls, multiple orthogonal methods\",\n      \"pmids\": [\"15853885\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RESA influences the dynamic microcirculatory behavior of ring-stage P. falciparum-infected RBCs. RESA-expressing Pf-RBCs showed decreased membrane fluctuations (diffraction phase microscopy), reduced transit velocity in microfluidic experiments, and impaired traversal in microsphere filtration at febrile temperature. These effects were RESA-dependent and fever-enhanced.\",\n      \"method\": \"Diffraction phase microscopy; microfluidic transit assay; microsphere filtration; comparison of RESA-expressing vs. RESA-disrupted isogenic parasite lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic RESA-KO comparison using multiple biophysical assays (diffraction phase microscopy, microfluidics, filtration), single lab\",\n      \"pmids\": [\"22937223\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Trafficking of RESA to the host erythrocyte cytosol requires both an appropriate N-terminal transport signal (hydrophobic stretch acting as a non-canonical secretory signal) AND correct timing of expression (schizont stage under the RESA promoter). Expression of RESA-GFP under a trophozoite-specific promoter mistargeted the chimeric protein to the parasitophorous vacuole, whereas expression under the native RESA promoter in schizont stages enabled correct trafficking to the host erythrocyte.\",\n      \"method\": \"Transfection of P. falciparum with RESA-GFP chimeric constructs under different promoters; fluorescence microscopy; stage-specific expression analysis\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging of trafficking with promoter-swap experiment defining two requirements, single lab but clean functional consequence\",\n      \"pmids\": [\"15385514\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An extended PRESAN domain (comprising the PRESAN domain and preceding sequence) of PHISTb proteins is sufficient to localize proteins to the erythrocyte periphery and functions as a cytoskeleton-binding domain. This domain was validated in RESA, identifying a second cytoskeleton-binding domain that functions independently of RESA's known spectrin-binding domain.\",\n      \"method\": \"Subcellular localization of truncated/chimeric constructs by microscopy; Triton X-100 fractionation for cytoskeletal association; domain deletion and swap experiments validated in RESA\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization with functional domain validation in RESA, single lab, single method set\",\n      \"pmids\": [\"25106850\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Loss of RESA (in parasites with a large chromosome 1 deletion) significantly affects the ability of parasitized RBCs to adhere under flow conditions to CD36, as measured by a competitive flow-based adhesion assay.\",\n      \"method\": \"Flow-based cytoadhesion assay using parasite lines lacking specific proteins including RESA\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single adhesion assay, RESA loss achieved via large chromosomal deletion (not targeted KO), potentially confounded by loss of other genes on the deletion\",\n      \"pmids\": [\"11918556\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The RESA gene consists of two exons with a short intron near the 5' end of the coding region. A hydrophobic amino acid segment encoded by the 3' end of exon 1 is consistent with a trafficking signal sequence. Restriction fragment length polymorphisms define two different alleles represented by isolates FC27 and NF7.\",\n      \"method\": \"Nucleotide sequencing; gene structure analysis; RFLP analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete gene sequencing with structural analysis, foundational gene structure study\",\n      \"pmids\": [\"3537955\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Expression of RESA is prevented in the P. falciparum isolate FCR3 because the 5' end of the RESA gene has been inverted and partly deleted, with a telomere added to it. This represents a subtelomeric deletion mechanism silencing the gene.\",\n      \"method\": \"Southern blotting; molecular cloning; sequence analysis of the FCR3 RESA locus\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct molecular characterization of gene structure alteration explaining lack of expression, single lab\",\n      \"pmids\": [\"2677678\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RESA, as a representative exported protein, failed to be transported across the parasitophorous vacuolar membrane to the host erythrocyte in parasites in which the rhoptry protein RON3 was conditionally disrupted, demonstrating that RON3 is required for functional PTEX-mediated export of RESA.\",\n      \"method\": \"Conditional disruption of RON3; immunofluorescence assay monitoring RESA localization in RON3-deficient parasites\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean conditional KO with direct localization readout for RESA export, single lab, single method for RESA-specific finding\",\n      \"pmids\": [\"31289187\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A crystal structure of two Fab domains of human monoclonal antibody B1E11K in complex with RESA showed binding to a repeating epitope motif in a head-to-head conformation involving affinity-matured homotypic interactions between the two Fab domains.\",\n      \"method\": \"X-ray crystallography of Fab-RESA complex; human monoclonal antibody isolation by single B cell activation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation of binding mode, single lab but rigorous structural method\",\n      \"pmids\": [\"39817720\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ultrastructural expansion microscopy (U-ExM) confirmed RESA localization in dense granules of P. falciparum 3D7 merozoites and demonstrated translocation of RESA to the infected erythrocyte membrane in early ring-stage parasites, consistent with immunoelectron microscopy data.\",\n      \"method\": \"Ultrastructural expansion microscopy (U-ExM) with anti-RESA mAb and NHS-ester protein staining\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by novel expansion microscopy method consistent with established IEM data, single lab\",\n      \"pmids\": [\"39732432\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Using RESA localization as a proxy marker for dense granule formation, dense granule biogenesis commences approximately 37 minutes prior to schizont egress.\",\n      \"method\": \"Time-lapse fluorescence microscopy of RESA-expressing parasites to track DG formation timing\",\n      \"journal\": \"Microbiology (Reading, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct live-cell imaging using RESA as DG marker, single lab, RESA used as proxy rather than primary subject\",\n      \"pmids\": [\"37647112\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"RESA (PF3D7_0102200) is a ~155 kDa protein stored in merozoite dense granules that is released into the parasitophorous vacuole after erythrocyte invasion (not before), traffics to the inner face of the host erythrocyte membrane in a process requiring both its N-terminal hydrophobic signal sequence and schizont-stage expression timing, where it binds to repeat 16 of beta-spectrin via a defined 108-amino-acid domain (residues 663-770) as well as through an independent PRESAN-domain interaction, stabilizes spectrin tetramers against dissociation, reduces ring-stage RBC deformability and microcirculatory transit especially at febrile temperatures, protects the erythrocyte cytoskeleton from heat-induced damage, suppresses reinvasion of already-parasitized cells, and is phosphorylated on serine/threonine by an erythrocyte membrane kinase upon membrane association.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RESA (PF3D7_0102200) is a Plasmodium falciparum ring-stage antigen that remodels the host erythrocyte cytoskeleton to alter the mechanical and thermal stability of infected red cells [#3, #9]. Encoded by a two-exon gene whose 3' end of exon 1 specifies a hydrophobic trafficking signal [#15], RESA is synthesized during the schizont stage and stored in merozoite dense granules [#1, #19], from which it is discharged into the parasitophorous vacuole space only after erythrocyte invasion rather than at merozoite attachment [#2]. Correct delivery to the host erythrocyte cytosol requires both this N-terminal transport signal and schizont-stage expression timing [#12], and export across the parasitophorous vacuolar membrane depends on functional PTEX-mediated transport gated by the rhoptry protein RON3 [#17]. At the cytoplasmic face of the erythrocyte membrane skeleton [#4], RESA becomes Triton X-100-insoluble and binds spectrin, co-sedimenting with the actin-spectrin-band 4.1 complex and co-precipitating with spectrin [#3]; it engages repeat 16 of beta-spectrin through residues 663-770 near the labile dimer-dimer self-association site, and stabilizes spectrin tetramers against dissociation [#8]. A second, independent cytoskeleton-binding activity resides in an extended PRESAN domain [#13], while an internal 48-amino-acid segment between the two repeat blocks mediates membrane association independently of the tandem repeats [#6]. Upon membrane association RESA is phosphorylated on serine and minor threonine residues by an erythrocyte membrane kinase rather than a parasite enzyme [#5]. Functionally, isogenic gene-disruption studies show RESA reduces ring-stage RBC deformability and microcirculatory transit, effects that are enhanced at febrile temperature [#9, #11], and protects the infected-cell cytoskeleton against heat-induced vesiculation and fragmentation [#7, #10]; RESA is not required for merozoite invasion, but erythrocytes pre-loaded with the spectrin-binding fragment resist reinvasion [#8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing where RESA resides in the merozoite and infected cell was the first step in defining its stage of action, showing it is a stored protein that relocates to the erythrocyte membrane upon invasion.\",\n      \"evidence\": \"Immunoelectron microscopy with protein A gold plus Triton X-100 fractionation in P. falciparum\",\n      \"pmids\": [\"3894564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise granule identity (microneme vs dense granule) unresolved at this stage\", \"Mechanism of membrane insolubility transition undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Determining the gene structure identified a hydrophobic exon 1 segment consistent with a trafficking signal and revealed allelic polymorphism, framing how RESA reaches the erythrocyte.\",\n      \"evidence\": \"Nucleotide sequencing, gene structure analysis, and RFLP analysis in P. falciparum\",\n      \"pmids\": [\"3537955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal function not experimentally tested here\", \"Functional significance of allelic variation unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Explaining why isolate FCR3 lacks RESA showed the locus is silenced by subtelomeric inversion/deletion, providing a natural RESA-negative background for functional comparison.\",\n      \"evidence\": \"Southern blotting, cloning, and sequence analysis of the FCR3 RESA locus\",\n      \"pmids\": [\"2677678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address RESA's normal function\", \"Other genes potentially affected by the chromosomal rearrangement not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3\"}]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Refining the granule assignment corrected the earlier microneme localization, placing RESA specifically in dense granules and clarifying its secretion compartment.\",\n      \"evidence\": \"Immunoelectron microscopy in P. falciparum\",\n      \"pmids\": [\"2209790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing and route of granule discharge not yet established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Asking whether RESA is modified after export revealed it is phosphorylated by a host erythrocyte kinase specifically on membrane association, distinguishing a host-driven post-translational event from parasite enzymology.\",\n      \"evidence\": \"[gamma-32P]ATP labeling of IOVs, immunoprecipitation, phosphoamino acid analysis, and labeling of synchronized parasites in P. falciparum\",\n      \"pmids\": [\"2108327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the erythrocyte kinase unknown\", \"Functional consequence of phosphorylation undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defining the secretion route showed RESA is released from dense granules into the parasitophorous vacuole after invasion, not through rhoptry ducts at attachment, ordering its delivery relative to invasion.\",\n      \"evidence\": \"Postembedding immunolabeling electron microscopy of newly invaded erythrocytes in P. falciparum\",\n      \"pmids\": [\"1997422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery of vacuolar-to-cytosol transfer not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identifying the binding partner and topology established that RESA sits on the cytoplasmic face of the membrane skeleton and associates with spectrin, pinpointing its molecular target.\",\n      \"evidence\": \"Co-sedimentation with the actin-spectrin-band 4.1 complex, reciprocal co-IP with anti-spectrin, spectrin competition, IOV binding, and spectrin-depletion assays in P. falciparum\",\n      \"pmids\": [\"1852169\", \"2055301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding region on RESA not yet mapped\", \"Physiological consequence of spectrin binding not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Dissecting RESA's domains localized membrane binding to a 48-residue segment between the repeat blocks and demonstrated that recombinant RESA protects spectrin from heat-induced changes, linking binding to cytoskeletal stabilization.\",\n      \"evidence\": \"Deletion mutagenesis with IOV binding assays, fluorescence polarization of labeled spectrin, and heat-fragmentation comparison of RESA(+) vs RESA(-) infected cells in P. falciparum\",\n      \"pmids\": [\"7957755\", \"7984188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise spectrin residues contacted not yet defined\", \"RESA shown non-essential for invasion but reinvasion effect not yet tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Determining what governs export showed both the N-terminal hydrophobic signal and schizont-stage expression timing are required, since a trophozoite promoter mistargeted RESA-GFP to the vacuole.\",\n      \"evidence\": \"Transfection with RESA-GFP chimeras under different promoters and fluorescence microscopy in P. falciparum\",\n      \"pmids\": [\"15385514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular recognition of the signal by the export machinery not defined here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A targeted resa1 knockout with isogenic controls delivered the loss-of-function test, showing RESA is dispensable for invasion and basal rigidity but is required to protect infected cells against heat shock.\",\n      \"evidence\": \"resa1-KO with parental and resa3-KO controls, heat shock, invasion, rigidity, CD36 flow adhesion, and Saimiri infection assays in P. falciparum\",\n      \"pmids\": [\"15853885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting spectrin stabilization to heat protection at cellular scale not fully resolved\", \"Modest CD36 adhesion effect not mechanistically explained\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping RESA to beta-spectrin repeat 16 and demonstrating tetramer stabilization plus reinvasion resistance connected the molecular interaction to both mechanical stabilization and a barrier against superinfection.\",\n      \"evidence\": \"Defined spectrin-fragment binding, tetramer stabilization assays, resealed-fragment invasion assays, and optical-tweezers deformability with isogenic KO/revertant clones in P. falciparum\",\n      \"pmids\": [\"17468340\", \"17517609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RESA-spectrin contact not determined\", \"Relationship between deformability reduction and in vivo sequestration not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending the phenotype to microcirculatory behavior showed RESA reduces membrane fluctuations and transit and impairs traversal at febrile temperature, tying its cytoskeletal action to physiological blood flow.\",\n      \"evidence\": \"Diffraction phase microscopy, microfluidic transit, and microsphere filtration comparing isogenic RESA-expressing vs disrupted lines in P. falciparum\",\n      \"pmids\": [\"22937223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences for sequestration/pathogenesis not directly measured\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying an extended PRESAN cytoskeleton-binding domain revealed a second, spectrin-binding-independent membrane-anchoring activity in RESA.\",\n      \"evidence\": \"Localization of truncated/chimeric constructs, Triton X-100 fractionation, and domain swaps validated in RESA in P. falciparum\",\n      \"pmids\": [\"25106850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoskeletal ligand of the PRESAN domain not identified\", \"Single lab, single method set\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Testing export dependency showed RESA fails to reach the host erythrocyte when the rhoptry protein RON3 is conditionally disrupted, placing RESA export downstream of RON3-gated PTEX function.\",\n      \"evidence\": \"Conditional RON3 disruption with immunofluorescence tracking of RESA localization in P. falciparum\",\n      \"pmids\": [\"31289187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction of RESA with PTEX components not shown\", \"Single method for the RESA-specific readout\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Independent expansion microscopy re-confirmed dense-granule storage and ring-stage translocation of RESA to the erythrocyte membrane, corroborating decades-old immuno-EM with a modern method.\",\n      \"evidence\": \"Ultrastructural expansion microscopy with anti-RESA mAb in P. falciparum 3D7\",\n      \"pmids\": [\"39732432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No new mechanistic information beyond localization confirmation\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A crystal structure of the human antibody B1E11K bound to RESA's repeating epitope defined the immune-recognition mode via homotypic Fab-Fab interactions, characterizing RESA as an antigenic target.\",\n      \"evidence\": \"X-ray crystallography of a Fab-RESA complex with antibody from single B cell activation in P. falciparum\",\n      \"pmids\": [\"39817720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure covers a repeat epitope, not the spectrin-binding or PRESAN domains\", \"Protective significance of the antibody not established here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two independent cytoskeleton-binding activities (the 663-770 beta-spectrin site and the PRESAN domain) and host-kinase phosphorylation are integrated into RESA's mechanical and heat-protective effects, and whether these translate to in vivo pathogenesis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the RESA-spectrin interface\", \"Functional role of phosphorylation untested\", \"Relative contribution of spectrin-binding vs PRESAN domain to cellular phenotypes unquantified\", \"In vivo sequestration/virulence consequences not directly demonstrated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030507\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031090\", \"supporting_discovery_ids\": [1, 2, 19, 20]},\n      {\"term_id\": \"GO:0020020\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"GO:0030864\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0065003\", \"supporting_discovery_ids\": [8, 7]},\n      {\"term_id\": \"GO:0006612\", \"supporting_discovery_ids\": [12, 17]}\n    ],\n    \"complexes\": [\n      \"spectrin-actin-band 4.1 erythrocyte membrane skeleton (co-sedimentation) [#3]\"\n    ],\n    \"partners\": [\n      \"beta-spectrin (repeat 16; RESA residues 663-770) [#3, #8]\",\n      \"erythrocyte membrane serine/threonine kinase (phosphorylates RESA) [#5]\",\n      \"RON3 (required for PTEX-mediated export of RESA) [#17]\",\n      \"human monoclonal antibody B1E11K (binds RESA repeat epitope) [#18]\"\n    ],\n    \"other_free_text\": [\n      \"Stored in merozoite dense granules and discharged into the parasitophorous vacuole after invasion, not before [#1, #2]\",\n      \"Two-exon gene; hydrophobic exon 1 segment acts as a non-canonical trafficking signal; correct export requires this signal plus schizont-stage timing [#12, #15]\",\n      \"48-amino-acid membrane-binding domain between the repeat blocks; tandem repeats and large N-terminal deletions not required for binding [#6]\",\n      \"Reduces ring-stage RBC deformability and microcirculatory transit, effects enhanced at febrile temperature [#9, #11]\",\n      \"Protects infected-cell cytoskeleton from heat-induced vesiculation/fragmentation [#7, #10]\",\n      \"Dispensable for merozoite invasion; spectrin-binding fragment confers resistance to reinvasion [#7, #8, #10]\",\n      \"Silenced in isolate FCR3 by subtelomeric inversion/deletion [#16]\",\n      \"Modest effect on CD36 cytoadhesion under flow [#10, #14]\",\n      \"Used as a dense-granule biogenesis marker (~37 min before egress) [#20]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0102200","name":null,"product":"ring-infected erythrocyte surface antigen","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RESA","evaluation":null}