{"gene":"PF3D7_1036300","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2012,"finding":"The DBL domain of DBLMSP2 (PfMSPDBL2/PF10_0355) binds human erythrocytes; the recombinant DBL domain retains binding activity comparable to full-length parasite-derived protein, and metal cofactors enhance this erythrocyte binding. The crystal structure of the erythrocyte-binding DBL domain was solved to 2.09 Å, revealing a canonical boomerang-shaped α-helical core of three subdomains; polymorphic residues map to the surface predominantly in subdomains 1 and 2, while the cleft separating subdomains 1–2 from subdomain 3 and the groove between the two major helices of subdomain 3 are structurally conserved, indicating these regions are functionally important for receptor binding.","method":"Crystal structure determination (2.09 Å); recombinant protein expression and refolding; erythrocyte binding assays with recombinant DBL domain and parasite-derived full-length protein; metal cofactor titration experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro functional binding assay with both recombinant and native protein, multiple orthogonal methods in a single focused study","pmids":["22843685"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"DBLMSP2 directly and avidly binds human IgM via its DBL domain. This IgM-binding function is conserved across broadly diverged sequence variants (multiple allelic classes). IgM binding by DBLMSP2 inhibits overall IgG immunoreactivity of the protein in patient sera, suggesting IgM acts as a molecular shield masking the protein from the host humoral immune response. IgM binding did not detectably affect red blood cell invasion efficiency.","method":"Recombinant protein binding assays; transgenic parasite lines; population genomics of >400 isolates for conservation analysis; IgG immunoreactivity assays; red blood cell invasion assays (negative result for invasion effect)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with recombinant protein and transgenic parasites, conservation validated across >400 genomes, multiple orthogonal methods","pmids":["27226583"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Cryo-EM structural analysis showed that DBLMSP2 binds IgM in a distinct manner compared to DBLMSP, VAR2CSA, and TM284VAR1, with each protein engaging IgM through a different DBL domain–IgM interaction mode. DBLMSP2 (along with the other IgM-binding proteins) directly interferes with IgM-mediated complement activation in vitro.","method":"High-resolution cryo-electron microscopy; in vitro complement activation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with in vitro functional complement inhibition assay, single study but orthogonal structural and biochemical methods","pmids":["37156765"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Knockout of DBLMSP2 increased P. falciparum parasite sensitivity specifically to halofantrine, mefloquine, and lumefantrine (but not to unrelated antimalarials), demonstrating that DBLMSP2 modulates the parasite response to this class of structurally related drugs. Overexpression lowered sensitivity to the same drugs. A single C591S substitution within DBLMSP2 conferred an allele-specific effect on drug sensitivity: parasites expressing the derived (C591S) allele were less sensitive to halofantrine and related drugs, and outcompeted ancestral-allele parasites under drug pressure within a few generations.","method":"Knockout parasite lines; overexpression transgenic lines; allele-swap transgenic lines; IC50 drug sensitivity assays; growth competition experiments under drug pressure","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO and allele-specific transgenic lines with defined drug-sensitivity phenotype, multiple complementary genetic approaches in one study","pmids":["23587962"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Conditional overexpression of the gametocyte development protein GDV1 substantially increases the proportion of DBLMSP2-positive schizonts, and truncation of gdv1 completely abolishes DBLMSP2 expression, placing GDV1 as a positive regulator of DBLMSP2 expression. However, individual schizonts expressing DBLMSP2 are mostly distinct from those expressing AP2-G (the master regulator of sexual commitment), and engineered disruption or intact expression of DBLMSP2 in the majority of schizonts does not affect sexual commitment, early gametocyte development, or asexual multiplication rates.","method":"Conditional GDV1 overexpression system; gdv1 truncation lines; selection-linked integration to express intact or disrupted DBLMSP2; immunofluorescence co-localisation with HA-tagged AP2-G; gametocyte conversion rate assays; asexual growth rate assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple engineered transgenic lines with defined phenotypic readouts, orthogonal genetic approaches (overexpression, truncation, SLI), single lab but comprehensive experimental design","pmids":["38530030"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"DBLMSP2 (PF3D7_1036300) is a polymorphic merozoite surface protein whose DBL domain adopts a conserved three-subdomain α-helical fold that mediates erythrocyte binding (enhanced by metal cofactors) and, via a distinct structural mode, avidly binds human IgM to inhibit complement activation and shield the protein from IgG-mediated immunity; its expression in a discrete schizont subpopulation is positively regulated by GDV1 independently of sexual commitment, and modulation of its copy number or a C591S allelic variant specifically alters parasite sensitivity to halofantrine, mefloquine, and lumefantrine."},"narrative":{"mechanistic_narrative":"DBLMSP2 (PF3D7_1036300) is a polymorphic merozoite surface protein of the Duffy binding-like (DBL) domain family whose activities center on erythrocyte engagement and host immune evasion during the blood stage [PMID:22843685, PMID:27226583]. Its DBL domain adopts a canonical boomerang-shaped α-helical fold of three subdomains and binds human erythrocytes, an activity enhanced by metal cofactors; polymorphic residues cluster on the surface of subdomains 1 and 2 while the inter-subdomain cleft and the subdomain-3 groove are conserved and functionally important for receptor binding [PMID:22843685]. Through a structurally distinct mode captured by cryo-EM, the same DBL domain avidly binds human IgM in a manner conserved across broadly diverged allelic classes; this IgM binding masks the protein from IgG immunoreactivity in patient sera and interferes with IgM-mediated complement activation, functioning as an immune shield without detectably altering red blood cell invasion [PMID:27226583, PMID:37156765]. Expression of DBLMSP2 is restricted to a discrete schizont subpopulation that is positively regulated by GDV1 but is largely distinct from AP2-G-expressing schizonts and dispensable for sexual commitment and asexual growth [PMID:38530030]. Genetic modulation of DBLMSP2, including copy-number changes and a C591S substitution, specifically alters parasite sensitivity to the structurally related antimalarials halofantrine, mefloquine, and lumefantrine [PMID:23587962].","teleology":[{"year":2012,"claim":"Establishing whether DBLMSP2 engages host cells defined its role as a merozoite surface receptor-binding protein and revealed the structural basis of that interaction.","evidence":"Crystal structure of the DBL domain at 2.09 Å with recombinant and native erythrocyte-binding assays and metal cofactor titration in P. falciparum","pmids":["22843685"],"confidence":"High","gaps":["The erythrocyte receptor for DBLMSP2 was not identified","Functional consequence of erythrocyte binding for invasion or growth not resolved","Role of metal cofactor enhancement in vivo unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Discovery that the DBL domain avidly binds human IgM across allelic classes reframed DBLMSP2 as an immune-evasion molecule that shields itself from the IgG response rather than a simple invasion ligand.","evidence":"Recombinant and transgenic-parasite binding assays, population genomics of >400 isolates, IgG immunoreactivity and invasion assays in P. falciparum","pmids":["27226583"],"confidence":"High","gaps":["Molecular interface of the IgM interaction not defined at this stage","In vivo immune-shielding benefit not demonstrated","Relationship between IgM binding and erythrocyte binding unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Structural resolution of the DBLMSP2–IgM complex and a complement assay showed the interaction uses a distinct DBL–IgM mode and directly blocks complement activation, giving mechanistic teeth to the immune-shield model.","evidence":"High-resolution cryo-EM and in vitro complement activation assay in P. falciparum","pmids":["37156765"],"confidence":"High","gaps":["Contribution of complement inhibition to parasite survival in the host not tested","Whether IgM binding and complement blockade operate on the merozoite surface in vivo not shown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Genetic manipulation established that DBLMSP2 modulates parasite sensitivity to a specific chemical class of antimalarials, linking this surface protein to drug response and adaptive allele selection.","evidence":"Knockout, overexpression and C591S allele-swap lines with IC50 assays and growth competition under drug pressure in P. falciparum","pmids":["23587962"],"confidence":"High","gaps":["Mechanism connecting a surface DBL protein to drug sensitivity is unknown","No molecular link between the C591S variant and drug handling defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Defining the transcriptional control and cellular expression pattern of DBLMSP2 placed it downstream of GDV1 in a discrete schizont subpopulation while decoupling it from AP2-G-driven sexual commitment.","evidence":"Conditional GDV1 overexpression, gdv1 truncation, SLI lines, IFA co-localisation with HA-AP2-G, and conversion/growth assays in P. falciparum","pmids":["38530030"],"confidence":"High","gaps":["Biological purpose of the distinct DBLMSP2-positive schizont subpopulation unknown","Direct versus indirect regulation by GDV1 not distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The identity of the erythrocyte receptor and the mechanistic basis by which a surface DBL protein influences antimalarial drug sensitivity remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No erythrocyte receptor identified","No mechanism linking DBLMSP2 to halofantrine/mefloquine/lumefantrine handling","Functional role of the GDV1-regulated DBLMSP2-positive subpopulation undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["HUMAN IGM (HOST)","GDV1 (POSITIVE REGULATOR OF DBLMSP2 EXPRESSION)"],"other_free_text":["DBL domain adopts a boomerang-shaped three-subdomain α-helical fold; polymorphic residues map to subdomains 1 and 2, conserved cleft and subdomain-3 groove important for receptor binding [#0]","Erythrocyte binding by the DBL domain is enhanced by metal cofactors [#0]","IgM binding is conserved across broadly diverged allelic classes and masks the protein from IgG immunoreactivity [#1]","Modulation of copy number or a C591S allele specifically alters sensitivity to halofantrine, mefloquine, and lumefantrine [#3]","Expressed in a discrete schizont subpopulation largely distinct from AP2-G-expressing schizonts; dispensable for sexual commitment and asexual growth [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"22843685","id":"PMC_22843685","title":"Insights into Duffy binding-like domains through the crystal structure and function of the merozoite surface protein MSPDBL2 from Plasmodium falciparum.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22843685","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27226583","id":"PMC_27226583","title":"Binding of Plasmodium falciparum Merozoite Surface Proteins DBLMSP and DBLMSP2 to Human Immunoglobulin M Is Conserved among Broadly Diverged Sequence Variants.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27226583","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23587962","id":"PMC_23587962","title":"Modulation of PF10_0355 (MSPDBL2) alters Plasmodium falciparum response to antimalarial drugs.","date":"2013","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/23587962","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37156765","id":"PMC_37156765","title":"Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37156765","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39522520","id":"PMC_39522520","title":"Identification of complex Plasmodium falciparum genetic backgrounds circulating in Africa: a multicountry genomic epidemiology analysis.","date":"2024","source":"The Lancet. Microbe","url":"https://pubmed.ncbi.nlm.nih.gov/39522520","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35904009","id":"PMC_35904009","title":"Plasmodium falciparum merozoite invasion ligands, linked antimalarial resistance loci and ex vivo responses to antimalarials in The Gambia.","date":"2022","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/35904009","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfDBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38451924","id":"PMC_38451924","title":"Role for gene conversion in the evolution of cell-surface antigens of the malaria parasite Plasmodium falciparum.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/38451924","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38530030","id":"PMC_38530030","title":"Expression of the MSPDBL2 antigen in a discrete subset of Plasmodium falciparum schizonts is regulated by GDV1 but may not be linked to sexual commitment.","date":"2024","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/38530030","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41995169","id":"PMC_41995169","title":"Module-level recombination drives DBLMSP polymorphism and functional conservation in Plasmodium falciparum.","date":"2026","source":"Parasite (Paris, France)","url":"https://pubmed.ncbi.nlm.nih.gov/41995169","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DBLMSP2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7896,"output_tokens":1847,"usd":0.025697,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7014,"output_tokens":2732,"usd":0.051685,"stage2_stop_reason":"end_turn"},"total_usd":0.077382,"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\": 2012,\n      \"finding\": \"The DBL domain of DBLMSP2 (PfMSPDBL2/PF10_0355) binds human erythrocytes; the recombinant DBL domain retains binding activity comparable to full-length parasite-derived protein, and metal cofactors enhance this erythrocyte binding. The crystal structure of the erythrocyte-binding DBL domain was solved to 2.09 Å, revealing a canonical boomerang-shaped α-helical core of three subdomains; polymorphic residues map to the surface predominantly in subdomains 1 and 2, while the cleft separating subdomains 1–2 from subdomain 3 and the groove between the two major helices of subdomain 3 are structurally conserved, indicating these regions are functionally important for receptor binding.\",\n      \"method\": \"Crystal structure determination (2.09 Å); recombinant protein expression and refolding; erythrocyte binding assays with recombinant DBL domain and parasite-derived full-length protein; metal cofactor titration experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro functional binding assay with both recombinant and native protein, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"22843685\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DBLMSP2 directly and avidly binds human IgM via its DBL domain. This IgM-binding function is conserved across broadly diverged sequence variants (multiple allelic classes). IgM binding by DBLMSP2 inhibits overall IgG immunoreactivity of the protein in patient sera, suggesting IgM acts as a molecular shield masking the protein from the host humoral immune response. IgM binding did not detectably affect red blood cell invasion efficiency.\",\n      \"method\": \"Recombinant protein binding assays; transgenic parasite lines; population genomics of >400 isolates for conservation analysis; IgG immunoreactivity assays; red blood cell invasion assays (negative result for invasion effect)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with recombinant protein and transgenic parasites, conservation validated across >400 genomes, multiple orthogonal methods\",\n      \"pmids\": [\"27226583\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structural analysis showed that DBLMSP2 binds IgM in a distinct manner compared to DBLMSP, VAR2CSA, and TM284VAR1, with each protein engaging IgM through a different DBL domain–IgM interaction mode. DBLMSP2 (along with the other IgM-binding proteins) directly interferes with IgM-mediated complement activation in vitro.\",\n      \"method\": \"High-resolution cryo-electron microscopy; in vitro complement activation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with in vitro functional complement inhibition assay, single study but orthogonal structural and biochemical methods\",\n      \"pmids\": [\"37156765\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockout of DBLMSP2 increased P. falciparum parasite sensitivity specifically to halofantrine, mefloquine, and lumefantrine (but not to unrelated antimalarials), demonstrating that DBLMSP2 modulates the parasite response to this class of structurally related drugs. Overexpression lowered sensitivity to the same drugs. A single C591S substitution within DBLMSP2 conferred an allele-specific effect on drug sensitivity: parasites expressing the derived (C591S) allele were less sensitive to halofantrine and related drugs, and outcompeted ancestral-allele parasites under drug pressure within a few generations.\",\n      \"method\": \"Knockout parasite lines; overexpression transgenic lines; allele-swap transgenic lines; IC50 drug sensitivity assays; growth competition experiments under drug pressure\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO and allele-specific transgenic lines with defined drug-sensitivity phenotype, multiple complementary genetic approaches in one study\",\n      \"pmids\": [\"23587962\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional overexpression of the gametocyte development protein GDV1 substantially increases the proportion of DBLMSP2-positive schizonts, and truncation of gdv1 completely abolishes DBLMSP2 expression, placing GDV1 as a positive regulator of DBLMSP2 expression. However, individual schizonts expressing DBLMSP2 are mostly distinct from those expressing AP2-G (the master regulator of sexual commitment), and engineered disruption or intact expression of DBLMSP2 in the majority of schizonts does not affect sexual commitment, early gametocyte development, or asexual multiplication rates.\",\n      \"method\": \"Conditional GDV1 overexpression system; gdv1 truncation lines; selection-linked integration to express intact or disrupted DBLMSP2; immunofluorescence co-localisation with HA-tagged AP2-G; gametocyte conversion rate assays; asexual growth rate assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple engineered transgenic lines with defined phenotypic readouts, orthogonal genetic approaches (overexpression, truncation, SLI), single lab but comprehensive experimental design\",\n      \"pmids\": [\"38530030\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"DBLMSP2 (PF3D7_1036300) is a polymorphic merozoite surface protein whose DBL domain adopts a conserved three-subdomain α-helical fold that mediates erythrocyte binding (enhanced by metal cofactors) and, via a distinct structural mode, avidly binds human IgM to inhibit complement activation and shield the protein from IgG-mediated immunity; its expression in a discrete schizont subpopulation is positively regulated by GDV1 independently of sexual commitment, and modulation of its copy number or a C591S allelic variant specifically alters parasite sensitivity to halofantrine, mefloquine, and lumefantrine.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DBLMSP2 (PF3D7_1036300) is a polymorphic merozoite surface protein of the Duffy binding-like (DBL) domain family whose activities center on erythrocyte engagement and host immune evasion during the blood stage [#0, #1]. Its DBL domain adopts a canonical boomerang-shaped α-helical fold of three subdomains and binds human erythrocytes, an activity enhanced by metal cofactors; polymorphic residues cluster on the surface of subdomains 1 and 2 while the inter-subdomain cleft and the subdomain-3 groove are conserved and functionally important for receptor binding [#0]. Through a structurally distinct mode captured by cryo-EM, the same DBL domain avidly binds human IgM in a manner conserved across broadly diverged allelic classes; this IgM binding masks the protein from IgG immunoreactivity in patient sera and interferes with IgM-mediated complement activation, functioning as an immune shield without detectably altering red blood cell invasion [#1, #2]. Expression of DBLMSP2 is restricted to a discrete schizont subpopulation that is positively regulated by GDV1 but is largely distinct from AP2-G-expressing schizonts and dispensable for sexual commitment and asexual growth [#4]. Genetic modulation of DBLMSP2, including copy-number changes and a C591S substitution, specifically alters parasite sensitivity to the structurally related antimalarials halofantrine, mefloquine, and lumefantrine [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing whether DBLMSP2 engages host cells defined its role as a merozoite surface receptor-binding protein and revealed the structural basis of that interaction.\",\n      \"evidence\": \"Crystal structure of the DBL domain at 2.09 Å with recombinant and native erythrocyte-binding assays and metal cofactor titration in P. falciparum\",\n      \"pmids\": [\"22843685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The erythrocyte receptor for DBLMSP2 was not identified\", \"Functional consequence of erythrocyte binding for invasion or growth not resolved\", \"Role of metal cofactor enhancement in vivo unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that the DBL domain avidly binds human IgM across allelic classes reframed DBLMSP2 as an immune-evasion molecule that shields itself from the IgG response rather than a simple invasion ligand.\",\n      \"evidence\": \"Recombinant and transgenic-parasite binding assays, population genomics of >400 isolates, IgG immunoreactivity and invasion assays in P. falciparum\",\n      \"pmids\": [\"27226583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface of the IgM interaction not defined at this stage\", \"In vivo immune-shielding benefit not demonstrated\", \"Relationship between IgM binding and erythrocyte binding unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structural resolution of the DBLMSP2–IgM complex and a complement assay showed the interaction uses a distinct DBL–IgM mode and directly blocks complement activation, giving mechanistic teeth to the immune-shield model.\",\n      \"evidence\": \"High-resolution cryo-EM and in vitro complement activation assay in P. falciparum\",\n      \"pmids\": [\"37156765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of complement inhibition to parasite survival in the host not tested\", \"Whether IgM binding and complement blockade operate on the merozoite surface in vivo not shown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic manipulation established that DBLMSP2 modulates parasite sensitivity to a specific chemical class of antimalarials, linking this surface protein to drug response and adaptive allele selection.\",\n      \"evidence\": \"Knockout, overexpression and C591S allele-swap lines with IC50 assays and growth competition under drug pressure in P. falciparum\",\n      \"pmids\": [\"23587962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting a surface DBL protein to drug sensitivity is unknown\", \"No molecular link between the C591S variant and drug handling defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining the transcriptional control and cellular expression pattern of DBLMSP2 placed it downstream of GDV1 in a discrete schizont subpopulation while decoupling it from AP2-G-driven sexual commitment.\",\n      \"evidence\": \"Conditional GDV1 overexpression, gdv1 truncation, SLI lines, IFA co-localisation with HA-AP2-G, and conversion/growth assays in P. falciparum\",\n      \"pmids\": [\"38530030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological purpose of the distinct DBLMSP2-positive schizont subpopulation unknown\", \"Direct versus indirect regulation by GDV1 not distinguished\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the erythrocyte receptor and the mechanistic basis by which a surface DBL protein influences antimalarial drug sensitivity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No erythrocyte receptor identified\", \"No mechanism linking DBLMSP2 to halofantrine/mefloquine/lumefantrine handling\", \"Functional role of the GDV1-regulated DBLMSP2-positive subpopulation undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0019865\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0042783\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0006956\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Human IgM (host)\",\n      \"GDV1 (positive regulator of DBLMSP2 expression)\"\n    ],\n    \"other_free_text\": [\n      \"DBL domain adopts a boomerang-shaped three-subdomain α-helical fold; polymorphic residues map to subdomains 1 and 2, conserved cleft and subdomain-3 groove important for receptor binding [#0]\",\n      \"Erythrocyte binding by the DBL domain is enhanced by metal cofactors [#0]\",\n      \"IgM binding is conserved across broadly diverged allelic classes and masks the protein from IgG immunoreactivity [#1]\",\n      \"Modulation of copy number or a C591S allele specifically alters sensitivity to halofantrine, mefloquine, and lumefantrine [#3]\",\n      \"Expressed in a discrete schizont subpopulation largely distinct from AP2-G-expressing schizonts; dispensable for sexual commitment and asexual growth [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1036300","name":null,"product":"duffy binding-like merozoite surface protein 2","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DBLMSP2","evaluation":null}