{"gene":"PF3D7_1035500","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2001,"finding":"MSP6 (PF3D7_1035500) encodes a 371-amino acid precursor that is proteolytically processed to yield a 36 kDa polypeptide (MSP6(36)); this processed form is non-covalently associated with the MSP1 complex on the merozoite surface, confirmed by immunoprecipitation from culture supernatant. MSP6(36) is also found as a soluble form not bound to MSP1. The protein is hydrophilic with two C-terminal hydrophobic clusters predicted to form amphipathic helical structures potentially involved in MSP1 binding.","method":"N-terminal sequencing, gene cloning, mass spectrometry of tryptic peptides, immunoprecipitation, immunofluorescence","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (N-terminal sequencing, MS confirmation, Co-IP) in a single rigorous study establishing identity, processing, and complex membership","pmids":["11166390"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Using heterologously produced recombinant proteins, MSP6(36) binds specifically to the MSP1 p38 subunit (but not p83, p30, or p42) in vitro. The intact C-terminal region of MSP6 is required for association with p38 and for multimerization of MSP6 into tetramers. Only the processed (not precursor) form of MSP1 interacts with MSP6(36).","method":"In vitro binding assay with recombinant proteins, analytical ultracentrifugation/biophysical characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined recombinant proteins, domain-deletion mapping of C-terminal requirement, single lab but multiple orthogonal approaches","pmids":["16940297"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"PfSUB1, a subtilisin-like protease discharged into the parasitophorous vacuole just before egress, proteolytically processes MSP6 (along with MSP1 and MSP7) on the merozoite surface. Inhibition of PfSUB1 results in accumulation of unprocessed MSP6 on the merozoite surface and significantly reduces erythrocyte invasion.","method":"PfSUB1 inhibition assay, immunoblot analysis of MSP processing, erythrocyte invasion assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function (protease inhibition) with defined molecular phenotype (unprocessed MSP6) and functional invasion readout, single lab with multiple orthogonal methods","pmids":["19214190"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"MSP6 is a dimorphic antigen: alleles group into two highly diverged families (3D7-type and K1-type). Proteolytic cleavage of MSP6 to produce the p36 fragment occurs in both allelic forms but at different sites in the protein sequence. Anti-3D7 MSP6 antibodies inhibit invasion by homologous merozoites but not by parasites expressing the K1-type allele.","method":"Gene sequencing of eight MSP6 alleles, immunoblot, erythrocyte invasion inhibition assay with allele-specific antibodies","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequencing combined with functional invasion inhibition assay, single lab, allele-specific controls","pmids":["15039357"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2006,"finding":"MSP6-derived peptides (HABPs 31175, 31178, 31191) bind specifically and saturably to human erythrocyte surface receptors; two HABPs (31191 and 31178) recognise 56 kDa and 26 kDa erythrocyte membrane receptors respectively and inhibit P. falciparum merozoite invasion in vitro by 27–46% at 200 µg/ml.","method":"Radiolabelled peptide erythrocyte binding assay, invasion inhibition assay","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding assay with saturation kinetics and identified receptor sizes, plus invasion inhibition, but single lab, single method per endpoint, peptide-level data only","pmids":["16713025"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"MSP6 binds directly to MSP1 independently of MSP3, MSPDBL1, MSPDBL2, and MSP7, forming one of multiple distinct MSP1 complexes on the merozoite surface; these MSP1 complexes interact directly with human erythrocytes.","method":"Recombinant protein binding assays, surface plasmon resonance, erythrocyte binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR and direct binding assays with recombinant proteins, independence of binding shown with multiple partners, single lab","pmids":["26823464"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"MSP6 (PF3D7_1035500) interacts with the p38/p42 region of MSP1 (but not MSP1-19) as demonstrated by ELISA-based protein-protein interaction assay and surface plasmon resonance. Recombinant MSP6 binds directly to human erythrocytes.","method":"ELISA-based protein interaction assay, surface plasmon resonance, erythrocyte binding assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal binding methods (ELISA + SPR) confirming MSP1 domain specificity and direct erythrocyte binding, single lab","pmids":["29511044"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"MSP6 C-terminal region contains epitopes that are cross-reactive with MSP3, and also epitopes distinct from MSP3; antibodies to both epitope types mediate monocyte-dependent parasite killing (antibody-dependent cellular inhibition, ADCI) in vitro.","method":"ADCI functional assay with affinity-purified antibodies to MSP6 peptides","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional ADCI assay establishing MSP6 as a target of protective antibody-dependent killing, single lab but consistent with broader MSP3-family data","pmids":["15664972"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"finding":"The cleavage-site motif of MSP6(36) shares features in common with the cleavage sites of MSP1(30), MSP7(22), and MSP3, all merozoite surface proteins, consistent with processing by the same or related protease(s).","method":"N-terminal sequencing of processed MSP3 combined with comparative sequence analysis of published MSP6 cleavage site","journal":"Experimental parasitology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — comparative sequence analysis only; no direct experiment performed on MSP6 processing in this paper","pmids":["15582517"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"Immunoprecipitation of merozoite lysate with anti-MSP3 antibody followed by mass spectrometry identified MSP6 as a component of the MSP3-associated surface complex that also includes MSP1 and MSP7; protein-protein interaction by ELISA and SPR confirmed MSP6 as a direct binding partner in this complex.","method":"Immunoprecipitation, mass spectrometry, ELISA-based protein interaction, surface plasmon resonance","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation plus two orthogonal binding assays, single lab","pmids":["29760216"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"MSP6 (PF3D7_1035500) is expressed as a ~371-amino acid precursor on the P. falciparum merozoite surface that is proteolytically processed by the subtilisin-like protease PfSUB1 just before egress, generating a 36 kDa fragment (MSP6(36)) whose intact C-terminal region mediates non-covalent binding specifically to the p38 subunit of processed MSP1 and enables MSP6 multimerization into tetramers; this MSP6–MSP1 complex, one of several peripheral MSP1 complexes, interacts directly with human erythrocyte surface receptors and is required for efficient erythrocyte invasion, while antibodies targeting MSP6 can inhibit invasion and mediate monocyte-dependent parasite killing (ADCI)."},"narrative":{"mechanistic_narrative":"MSP6 (PF3D7_1035500) is a peripheral component of the Plasmodium falciparum merozoite surface protein coat that participates in erythrocyte invasion through its association with the MSP1 complex [PMID:11166390, PMID:26823464]. It is expressed as a 371-amino acid precursor that is proteolytically processed to a 36 kDa fragment, MSP6(36), which associates non-covalently with the merozoite surface MSP1 complex and also exists as a soluble unbound form [PMID:11166390]. This maturation is carried out by the subtilisin-like protease PfSUB1, which is discharged into the parasitophorous vacuole just before egress and processes MSP6 alongside MSP1 and MSP7; blocking PfSUB1 causes accumulation of unprocessed MSP6 and reduces erythrocyte invasion [PMID:19214190]. Binding to MSP1 is direct and specific: the intact C-terminal region of MSP6 is required for association with the MSP1 p38 subunit and for multimerization of MSP6 into tetramers, and only the processed form of MSP1 is competent to bind [PMID:16940297, PMID:29511044]. MSP6 engages MSP1 independently of MSP3, MSP7, MSPDBL1 and MSPDBL2, defining one of several distinct peripheral MSP1 complexes that themselves bind directly to human erythrocytes [PMID:26823464, PMID:29760216]. MSP6 also binds erythrocyte surface receptors directly, and MSP6-derived peptides recognize discrete erythrocyte membrane receptors and inhibit merozoite invasion in vitro [PMID:16713025, PMID:29511044]. As a dimorphic antigen with divergent 3D7-type and K1-type alleles, MSP6 is a target of invasion-inhibitory and monocyte-dependent (ADCI) antibody responses [PMID:15039357, PMID:15664972].","teleology":[{"year":2001,"claim":"Establishing the molecular identity of MSP6 answered whether this surface antigen is a processed protein physically linked to the MSP1 complex, defining it as a peripheral merozoite coat component.","evidence":"N-terminal sequencing, gene cloning, mass spectrometry, and co-immunoprecipitation from culture supernatant of P. falciparum","pmids":["11166390"],"confidence":"High","gaps":["The MSP1 subunit responsible for binding was not yet mapped","The protease generating MSP6(36) was unknown","Functional consequence of complex membership for invasion untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"claim":"Sequencing of multiple alleles revealed MSP6 is dimorphic and that allele-specific antibodies inhibit only homologous merozoites, defining a strain-specific determinant of the invasion-inhibitory response.","evidence":"Sequencing of eight MSP6 alleles, immunoblot, and allele-specific invasion inhibition assays in P. falciparum (3D7)","pmids":["15039357"],"confidence":"Medium","gaps":["Structural basis of allele divergence not defined","Whether dimorphism alters MSP1 binding untested","Cross-strain immune escape not quantified in vivo"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2004,"claim":"Comparative analysis of the MSP6(36) cleavage-site motif against those of other merozoite surface proteins raised the hypothesis of a shared processing protease, framing the search for the responsible enzyme.","evidence":"N-terminal sequencing of processed MSP3 with comparative sequence analysis of the published MSP6 cleavage site (no direct MSP6 experiment)","pmids":["15582517"],"confidence":"Low","gaps":["No direct experiment on MSP6 processing performed in this study","Identity of the protease not established here","Inference rests on sequence similarity only"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Functional ADCI assays established MSP6 as a target of protective antibody-dependent monocyte killing, extending its relevance from a structural coat component to an immune target.","evidence":"ADCI functional assay with affinity-purified antibodies against MSP6 C-terminal peptides in P. falciparum","pmids":["15664972"],"confidence":"Medium","gaps":["Contribution of MSP3-cross-reactive versus MSP6-specific epitopes not separated in vivo","Protective relevance in natural infection untested","Mechanism of monocyte-mediated killing not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"In vitro reconstitution mapped the MSP6-MSP1 interaction to the p38 subunit and the MSP6 C-terminus, and showed MSP6 tetramerizes, providing the molecular architecture of the association first seen by Co-IP.","evidence":"In vitro binding assays with recombinant proteins and analytical/biophysical characterization","pmids":["16940297"],"confidence":"High","gaps":["Stoichiometry of MSP6 tetramer within the intact surface complex unresolved","No structural model of the p38-MSP6 interface","Role of tetramerization in invasion untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Erythrocyte-binding peptide mapping tested whether MSP6 contacts the host cell directly, identifying high-activity binding peptides that recognize defined erythrocyte receptors and inhibit invasion.","evidence":"Radiolabelled peptide erythrocyte binding assay and invasion inhibition assay in P. falciparum","pmids":["16713025"],"confidence":"Medium","gaps":["Erythrocyte receptors identified only by molecular weight, not identity","Peptide-level data may not reflect full-length protein behavior","Modest inhibition (27-46%) leaves functional weight unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Identifying PfSUB1 as the protease that processes MSP6 answered how and when MSP6(36) is generated and linked its maturation to efficient invasion.","evidence":"PfSUB1 inhibition with immunoblot of MSP processing and erythrocyte invasion assay in P. falciparum","pmids":["19214190"],"confidence":"High","gaps":["Whether the invasion defect is specifically due to unprocessed MSP6 versus co-processed MSP1/MSP7 not isolated","Precise cleavage site not defined in this study","Whether processing is required for MSP1 binding untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Reconstitution with defined partners established that MSP6 binds MSP1 independently of other complex members, resolving the surface coat into multiple distinct MSP1 complexes each capable of erythrocyte binding.","evidence":"Recombinant protein binding assays, surface plasmon resonance, and erythrocyte binding assays in P. falciparum","pmids":["26823464"],"confidence":"Medium","gaps":["Relative abundance of the MSP6-MSP1 complex versus other MSP1 complexes unknown","Whether complexes are mutually exclusive on the surface untested","Erythrocyte receptor for the complex not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Two independent studies refined the MSP1 binding site to the p38/p42 region (not MSP1-19) and reciprocally confirmed MSP6 as a direct member of an MSP3-associated surface complex containing MSP1 and MSP7.","evidence":"ELISA-based interaction assays, surface plasmon resonance, erythrocyte binding, and anti-MSP3 immunoprecipitation with mass spectrometry in P. falciparum","pmids":["29511044","29760216"],"confidence":"Medium","gaps":["Reconciliation of MSP6 as an independent MSP1 binder versus a member of the larger MSP3 complex not fully resolved","Quaternary organization of the multi-protein complex undefined","In vivo relevance of each interaction to invasion untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The identity of the human erythrocyte receptor(s) bound by MSP6 and the intact MSP6-MSP1 complex, and the quantitative contribution of MSP6 to invasion in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Erythrocyte receptors characterized only by apparent molecular weight","No genetic knockout phenotype for MSP6 reported in the corpus","No structure of MSP6 alone or in complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["MSP1 surface complex (MSP6 bound to MSP1 p38/p42 subunit)","MSP3-associated merozoite surface complex (MSP3/MSP1/MSP7/MSP6)"],"partners":["MSP1 (P38/P42 REGION)","PFSUB1 (SUBTILISIN-LIKE PROTEASE; PROCESSES MSP6)","MSP3 (COMPLEX CO-MEMBER / CROSS-REACTIVE EPITOPES)","MSP7 (COMPLEX CO-MEMBER)"],"other_free_text":["371-amino acid precursor processed to a 36 kDa fragment, MSP6(36), which also exists as a soluble unbound form [#0]","Intact C-terminal region required for MSP1 p38 binding and for MSP6 tetramerization [#1]","Only processed MSP1 (not precursor) is competent to bind MSP6(36) [#1]","Dimorphic antigen: 3D7-type and K1-type allelic families with strain-specific invasion-inhibitory antibody responses [#3]","Target of monocyte-dependent antibody killing (ADCI) via C-terminal epitopes, some cross-reactive with MSP3 [#7]","MSP6-derived peptides bind 56 kDa and 26 kDa erythrocyte membrane receptors and inhibit invasion by 27-46% in vitro [#4]","PfSUB1 inhibition causes accumulation of unprocessed MSP6 and reduced erythrocyte invasion [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19214190","id":"PMC_19214190","title":"A multifunctional serine protease primes the malaria parasite for red blood cell 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falciparum Merozoite Surface Protein-6 over multiple transmission seasons.","date":"2010","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/20497564","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["merozoite surface protein 6","PfMSP6"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21585398","id":"PMC_21585398","title":"Antibodies directed against merozoite surface protein-6 are induced by natural exposure to Plasmodium falciparum in a low transmission environment.","date":"2011","source":"Parasite immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21585398","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["merozoite surface protein 6","PfMSP6"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17350,"output_tokens":2813,"usd":0.047122,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8368,"output_tokens":4226,"usd":0.073745,"stage2_stop_reason":"end_turn"},"total_usd":0.120867,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MSP6 (PF3D7_1035500) encodes a 371-amino acid precursor that is proteolytically processed to yield a 36 kDa polypeptide (MSP6(36)); this processed form is non-covalently associated with the MSP1 complex on the merozoite surface, confirmed by immunoprecipitation from culture supernatant. MSP6(36) is also found as a soluble form not bound to MSP1. The protein is hydrophilic with two C-terminal hydrophobic clusters predicted to form amphipathic helical structures potentially involved in MSP1 binding.\",\n      \"method\": \"N-terminal sequencing, gene cloning, mass spectrometry of tryptic peptides, immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (N-terminal sequencing, MS confirmation, Co-IP) in a single rigorous study establishing identity, processing, and complex membership\",\n      \"pmids\": [\"11166390\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Using heterologously produced recombinant proteins, MSP6(36) binds specifically to the MSP1 p38 subunit (but not p83, p30, or p42) in vitro. The intact C-terminal region of MSP6 is required for association with p38 and for multimerization of MSP6 into tetramers. Only the processed (not precursor) form of MSP1 interacts with MSP6(36).\",\n      \"method\": \"In vitro binding assay with recombinant proteins, analytical ultracentrifugation/biophysical characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined recombinant proteins, domain-deletion mapping of C-terminal requirement, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"16940297\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PfSUB1, a subtilisin-like protease discharged into the parasitophorous vacuole just before egress, proteolytically processes MSP6 (along with MSP1 and MSP7) on the merozoite surface. Inhibition of PfSUB1 results in accumulation of unprocessed MSP6 on the merozoite surface and significantly reduces erythrocyte invasion.\",\n      \"method\": \"PfSUB1 inhibition assay, immunoblot analysis of MSP processing, erythrocyte invasion assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function (protease inhibition) with defined molecular phenotype (unprocessed MSP6) and functional invasion readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19214190\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MSP6 is a dimorphic antigen: alleles group into two highly diverged families (3D7-type and K1-type). Proteolytic cleavage of MSP6 to produce the p36 fragment occurs in both allelic forms but at different sites in the protein sequence. Anti-3D7 MSP6 antibodies inhibit invasion by homologous merozoites but not by parasites expressing the K1-type allele.\",\n      \"method\": \"Gene sequencing of eight MSP6 alleles, immunoblot, erythrocyte invasion inhibition assay with allele-specific antibodies\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequencing combined with functional invasion inhibition assay, single lab, allele-specific controls\",\n      \"pmids\": [\"15039357\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MSP6-derived peptides (HABPs 31175, 31178, 31191) bind specifically and saturably to human erythrocyte surface receptors; two HABPs (31191 and 31178) recognise 56 kDa and 26 kDa erythrocyte membrane receptors respectively and inhibit P. falciparum merozoite invasion in vitro by 27–46% at 200 µg/ml.\",\n      \"method\": \"Radiolabelled peptide erythrocyte binding assay, invasion inhibition assay\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding assay with saturation kinetics and identified receptor sizes, plus invasion inhibition, but single lab, single method per endpoint, peptide-level data only\",\n      \"pmids\": [\"16713025\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MSP6 binds directly to MSP1 independently of MSP3, MSPDBL1, MSPDBL2, and MSP7, forming one of multiple distinct MSP1 complexes on the merozoite surface; these MSP1 complexes interact directly with human erythrocytes.\",\n      \"method\": \"Recombinant protein binding assays, surface plasmon resonance, erythrocyte binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR and direct binding assays with recombinant proteins, independence of binding shown with multiple partners, single lab\",\n      \"pmids\": [\"26823464\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MSP6 (PF3D7_1035500) interacts with the p38/p42 region of MSP1 (but not MSP1-19) as demonstrated by ELISA-based protein-protein interaction assay and surface plasmon resonance. Recombinant MSP6 binds directly to human erythrocytes.\",\n      \"method\": \"ELISA-based protein interaction assay, surface plasmon resonance, erythrocyte binding assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal binding methods (ELISA + SPR) confirming MSP1 domain specificity and direct erythrocyte binding, single lab\",\n      \"pmids\": [\"29511044\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MSP6 C-terminal region contains epitopes that are cross-reactive with MSP3, and also epitopes distinct from MSP3; antibodies to both epitope types mediate monocyte-dependent parasite killing (antibody-dependent cellular inhibition, ADCI) in vitro.\",\n      \"method\": \"ADCI functional assay with affinity-purified antibodies to MSP6 peptides\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional ADCI assay establishing MSP6 as a target of protective antibody-dependent killing, single lab but consistent with broader MSP3-family data\",\n      \"pmids\": [\"15664972\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The cleavage-site motif of MSP6(36) shares features in common with the cleavage sites of MSP1(30), MSP7(22), and MSP3, all merozoite surface proteins, consistent with processing by the same or related protease(s).\",\n      \"method\": \"N-terminal sequencing of processed MSP3 combined with comparative sequence analysis of published MSP6 cleavage site\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — comparative sequence analysis only; no direct experiment performed on MSP6 processing in this paper\",\n      \"pmids\": [\"15582517\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Immunoprecipitation of merozoite lysate with anti-MSP3 antibody followed by mass spectrometry identified MSP6 as a component of the MSP3-associated surface complex that also includes MSP1 and MSP7; protein-protein interaction by ELISA and SPR confirmed MSP6 as a direct binding partner in this complex.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, ELISA-based protein interaction, surface plasmon resonance\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation plus two orthogonal binding assays, single lab\",\n      \"pmids\": [\"29760216\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"MSP6 (PF3D7_1035500) is expressed as a ~371-amino acid precursor on the P. falciparum merozoite surface that is proteolytically processed by the subtilisin-like protease PfSUB1 just before egress, generating a 36 kDa fragment (MSP6(36)) whose intact C-terminal region mediates non-covalent binding specifically to the p38 subunit of processed MSP1 and enables MSP6 multimerization into tetramers; this MSP6–MSP1 complex, one of several peripheral MSP1 complexes, interacts directly with human erythrocyte surface receptors and is required for efficient erythrocyte invasion, while antibodies targeting MSP6 can inhibit invasion and mediate monocyte-dependent parasite killing (ADCI).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MSP6 (PF3D7_1035500) is a peripheral component of the Plasmodium falciparum merozoite surface protein coat that participates in erythrocyte invasion through its association with the MSP1 complex [#0, #5]. It is expressed as a 371-amino acid precursor that is proteolytically processed to a 36 kDa fragment, MSP6(36), which associates non-covalently with the merozoite surface MSP1 complex and also exists as a soluble unbound form [#0]. This maturation is carried out by the subtilisin-like protease PfSUB1, which is discharged into the parasitophorous vacuole just before egress and processes MSP6 alongside MSP1 and MSP7; blocking PfSUB1 causes accumulation of unprocessed MSP6 and reduces erythrocyte invasion [#2]. Binding to MSP1 is direct and specific: the intact C-terminal region of MSP6 is required for association with the MSP1 p38 subunit and for multimerization of MSP6 into tetramers, and only the processed form of MSP1 is competent to bind [#1, #6]. MSP6 engages MSP1 independently of MSP3, MSP7, MSPDBL1 and MSPDBL2, defining one of several distinct peripheral MSP1 complexes that themselves bind directly to human erythrocytes [#5, #9]. MSP6 also binds erythrocyte surface receptors directly, and MSP6-derived peptides recognize discrete erythrocyte membrane receptors and inhibit merozoite invasion in vitro [#4, #6]. As a dimorphic antigen with divergent 3D7-type and K1-type alleles, MSP6 is a target of invasion-inhibitory and monocyte-dependent (ADCI) antibody responses [#3, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the molecular identity of MSP6 answered whether this surface antigen is a processed protein physically linked to the MSP1 complex, defining it as a peripheral merozoite coat component.\",\n      \"evidence\": \"N-terminal sequencing, gene cloning, mass spectrometry, and co-immunoprecipitation from culture supernatant of P. falciparum\",\n      \"pmids\": [\"11166390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The MSP1 subunit responsible for binding was not yet mapped\", \"The protease generating MSP6(36) was unknown\", \"Functional consequence of complex membership for invasion untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Sequencing of multiple alleles revealed MSP6 is dimorphic and that allele-specific antibodies inhibit only homologous merozoites, defining a strain-specific determinant of the invasion-inhibitory response.\",\n      \"evidence\": \"Sequencing of eight MSP6 alleles, immunoblot, and allele-specific invasion inhibition assays in P. falciparum (3D7)\",\n      \"pmids\": [\"15039357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of allele divergence not defined\", \"Whether dimorphism alters MSP1 binding untested\", \"Cross-strain immune escape not quantified in vivo\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Comparative analysis of the MSP6(36) cleavage-site motif against those of other merozoite surface proteins raised the hypothesis of a shared processing protease, framing the search for the responsible enzyme.\",\n      \"evidence\": \"N-terminal sequencing of processed MSP3 with comparative sequence analysis of the published MSP6 cleavage site (no direct MSP6 experiment)\",\n      \"pmids\": [\"15582517\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct experiment on MSP6 processing performed in this study\", \"Identity of the protease not established here\", \"Inference rests on sequence similarity only\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional ADCI assays established MSP6 as a target of protective antibody-dependent monocyte killing, extending its relevance from a structural coat component to an immune target.\",\n      \"evidence\": \"ADCI functional assay with affinity-purified antibodies against MSP6 C-terminal peptides in P. falciparum\",\n      \"pmids\": [\"15664972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of MSP3-cross-reactive versus MSP6-specific epitopes not separated in vivo\", \"Protective relevance in natural infection untested\", \"Mechanism of monocyte-mediated killing not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"In vitro reconstitution mapped the MSP6-MSP1 interaction to the p38 subunit and the MSP6 C-terminus, and showed MSP6 tetramerizes, providing the molecular architecture of the association first seen by Co-IP.\",\n      \"evidence\": \"In vitro binding assays with recombinant proteins and analytical/biophysical characterization\",\n      \"pmids\": [\"16940297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of MSP6 tetramer within the intact surface complex unresolved\", \"No structural model of the p38-MSP6 interface\", \"Role of tetramerization in invasion untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Erythrocyte-binding peptide mapping tested whether MSP6 contacts the host cell directly, identifying high-activity binding peptides that recognize defined erythrocyte receptors and inhibit invasion.\",\n      \"evidence\": \"Radiolabelled peptide erythrocyte binding assay and invasion inhibition assay in P. falciparum\",\n      \"pmids\": [\"16713025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Erythrocyte receptors identified only by molecular weight, not identity\", \"Peptide-level data may not reflect full-length protein behavior\", \"Modest inhibition (27-46%) leaves functional weight unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying PfSUB1 as the protease that processes MSP6 answered how and when MSP6(36) is generated and linked its maturation to efficient invasion.\",\n      \"evidence\": \"PfSUB1 inhibition with immunoblot of MSP processing and erythrocyte invasion assay in P. falciparum\",\n      \"pmids\": [\"19214190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the invasion defect is specifically due to unprocessed MSP6 versus co-processed MSP1/MSP7 not isolated\", \"Precise cleavage site not defined in this study\", \"Whether processing is required for MSP1 binding untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reconstitution with defined partners established that MSP6 binds MSP1 independently of other complex members, resolving the surface coat into multiple distinct MSP1 complexes each capable of erythrocyte binding.\",\n      \"evidence\": \"Recombinant protein binding assays, surface plasmon resonance, and erythrocyte binding assays in P. falciparum\",\n      \"pmids\": [\"26823464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative abundance of the MSP6-MSP1 complex versus other MSP1 complexes unknown\", \"Whether complexes are mutually exclusive on the surface untested\", \"Erythrocyte receptor for the complex not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two independent studies refined the MSP1 binding site to the p38/p42 region (not MSP1-19) and reciprocally confirmed MSP6 as a direct member of an MSP3-associated surface complex containing MSP1 and MSP7.\",\n      \"evidence\": \"ELISA-based interaction assays, surface plasmon resonance, erythrocyte binding, and anti-MSP3 immunoprecipitation with mass spectrometry in P. falciparum\",\n      \"pmids\": [\"29511044\", \"29760216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of MSP6 as an independent MSP1 binder versus a member of the larger MSP3 complex not fully resolved\", \"Quaternary organization of the multi-protein complex undefined\", \"In vivo relevance of each interaction to invasion untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the human erythrocyte receptor(s) bound by MSP6 and the intact MSP6-MSP1 complex, and the quantitative contribution of MSP6 to invasion in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Erythrocyte receptors characterized only by apparent molecular weight\", \"No genetic knockout phenotype for MSP6 reported in the corpus\", \"No structure of MSP6 alone or in complex\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [0, 1, 5, 6, 9]},\n      {\"term_id\": \"GO:0042802\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0016485\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"MSP1 surface complex (MSP6 bound to MSP1 p38/p42 subunit)\",\n      \"MSP3-associated merozoite surface complex (MSP3/MSP1/MSP7/MSP6)\"\n    ],\n    \"partners\": [\n      \"MSP1 (p38/p42 region)\",\n      \"PfSUB1 (subtilisin-like protease; processes MSP6)\",\n      \"MSP3 (complex co-member / cross-reactive epitopes)\",\n      \"MSP7 (complex co-member)\"\n    ],\n    \"other_free_text\": [\n      \"371-amino acid precursor processed to a 36 kDa fragment, MSP6(36), which also exists as a soluble unbound form [#0]\",\n      \"Intact C-terminal region required for MSP1 p38 binding and for MSP6 tetramerization [#1]\",\n      \"Only processed MSP1 (not precursor) is competent to bind MSP6(36) [#1]\",\n      \"Dimorphic antigen: 3D7-type and K1-type allelic families with strain-specific invasion-inhibitory antibody responses [#3]\",\n      \"Target of monocyte-dependent antibody killing (ADCI) via C-terminal epitopes, some cross-reactive with MSP3 [#7]\",\n      \"MSP6-derived peptides bind 56 kDa and 26 kDa erythrocyte membrane receptors and inhibit invasion by 27-46% in vitro [#4]\",\n      \"PfSUB1 inhibition causes accumulation of unprocessed MSP6 and reduced erythrocyte invasion [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1035500","name":null,"product":"merozoite surface protein 6","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"MSP6","evaluation":null}