{"gene":"PF3D7_1407000","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2004,"finding":"CCp3 (PfCCp3) is a sexually-stage-specific protein expressed in mature gametocytes with plasma membrane-associated localization; disruption of the PfCCp3 gene locus by homologous recombination produced parasites capable of forming oocyst sporozoites but blocked in salivary gland transition, establishing CCp3 as essential for mosquito-to-salivary-gland transmission.","method":"Targeted gene disruption by homologous recombination; transcript and protein expression analysis; cellular localization studies","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined transmission phenotype, replicated alongside sibling family members, localization confirmed by imaging","pmids":["15184503"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Abrogation of CCp3 (PfCCp3) by gene disruption leads to loss of PfCCp1 and PfCCp2 protein but not their transcripts, demonstrating co-dependent protein expression and suggesting that CCp3 is required for the stability or formation of a multi-protein complex containing these three proteins.","method":"Targeted gene disruption; Western blot and RT-PCR analysis of co-dependent expression in gene-disruptant parasites","journal":"Experimental parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with protein and mRNA level distinction, single lab, two orthogonal methods","pmids":["16388802"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"CCp3 (PfCCp3) is co-dependently expressed with PfCCp1 and PfCCp2 in the parasitophorous vacuole associated with the gametocyte plasma membrane (stages II–V), is present on both male and female gametocytes and macrogametes but absent from exflagellating microgametes, and targeted gene disruption of PfCCp3 inhibits parasite development in the mosquito vector.","method":"Immunofluorescence localization; stage-specific expression analysis; gene disruption phenotypic analysis; exflagellation assays with antibodies","journal":"International journal for parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IFA, gene disruption, functional assays), confirms and extends earlier findings from a separate lab","pmids":["17950739"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"CCp3 (PfCCp3) participates in multi-protein complexes with all six PfCCp family members in gametocytes, as demonstrated by co-immunoprecipitation from gametocyte lysates and affinity chromatography co-elution binding assays with recombinant PfCCp domains showing direct binding between distinct adhesion domains.","method":"Co-immunoprecipitation from gametocyte lysates; affinity chromatography co-elution binding assays with recombinant PfCCp domains; five gene-disruptant parasite lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus affinity binding assays with recombinant domains, multiple gene-disruptant lines, single lab with multiple orthogonal methods","pmids":["19304662"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"Knockdown of the WD40-repeat protein PfWLP1 in P. falciparum leads to reduced protein levels of PfCCp1 and PfCCp2 (key components of the PfCCp-based adhesion complex that includes CCp3), indicating that PfWLP1 is required for stability of the complex that contains CCp3 family members.","method":"Reverse genetics (knockdown); Western blot quantification of PfCCp1 and PfCCp2 levels; gametocyte exflagellation assays","journal":"Frontiers in cellular and infection microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown phenotype is shown for PfCCp1 and PfCCp2, not directly for CCp3 itself; single lab, indirect evidence for CCp3's place in the complex","pmids":["35923798"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"CCp3 (PF3D7_1407000) is a sexually-stage-specific, multi-domain adhesion protein expressed on the surface of gametocytes (stages II–V) and macrogametes in P. falciparum; it is a core member of a multi-protein complex formed by all six PfCCp family members in the parasitophorous vacuole, where the loss of CCp3 protein destabilizes PfCCp1 and PfCCp2 (co-dependent expression at the post-transcriptional level), and targeted disruption of the CCp3 gene blocks parasite development at the salivary gland transition step in the mosquito, establishing an essential role in mosquito-stage transmission."},"narrative":{"mechanistic_narrative":"CCp3 (PF3D7_1407000) is a sexual-stage adhesion protein of P. falciparum that is essential for parasite transmission through the mosquito vector [PMID:15184503, PMID:17950739]. It is expressed in mature gametocytes with plasma membrane-associated localization, is present in the parasitophorous vacuole associated with the gametocyte plasma membrane across stages II–V, and is found on both male and female gametocytes and on macrogametes but is absent from exflagellating microgametes [PMID:15184503, PMID:17950739]. CCp3 is a core member of a multi-protein adhesion complex that includes all six PfCCp family members, binding partner proteins through direct interactions between distinct adhesion domains [PMID:19304662]. Within this complex, CCp3 has an architectural role: targeted disruption of the CCp3 gene abolishes PfCCp1 and PfCCp2 protein without affecting their transcripts, demonstrating co-dependent, post-transcriptional stabilization of complex members [PMID:16388802]. Functionally, gene disruption permits oocyst sporozoite formation but blocks the salivary gland transition step, pinpointing CCp3 to a defined late mosquito-stage developmental transition [PMID:15184503]. Beyond its membership in and stabilization of this PfCCp complex and its transmission phenotype, no further biochemical activity of CCp3 has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Establishing whether CCp3 has a non-redundant biological function required a genetic test; knockout defined it as essential for a specific mosquito-stage transition.","evidence":"Targeted gene disruption by homologous recombination with transcript, protein, and localization analysis in P. falciparum gametocytes","pmids":["15184503"],"confidence":"High","gaps":["Molecular mechanism underlying the salivary gland transition block not defined","No biochemical activity assigned to the protein","Binding partners not yet identified at this stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Whether CCp3 acts alone or as part of an interdependent assembly was unknown; loss of CCp3 collapsing PfCCp1 and PfCCp2 protein but not transcript revealed a post-transcriptional co-dependence indicative of a shared complex.","evidence":"Gene disruption with Western blot versus RT-PCR comparison in disruptant parasites","pmids":["16388802"],"confidence":"Medium","gaps":["Does not resolve direct versus indirect stabilization","Single lab","Stoichiometry and full complex membership not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"The precise localization and cellular distribution of the co-dependent CCp assembly was refined, placing CCp3 in the gametocyte parathophorous vacuole at the plasma membrane across sexual stages and cell types.","evidence":"Immunofluorescence localization, stage-specific expression, exflagellation assays and gene disruption in P. falciparum","pmids":["17950739"],"confidence":"High","gaps":["Reason for absence from exflagellating microgametes unexplained","Does not define the adhesion target of the complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Whether the co-dependence reflected direct physical interaction was untested; reciprocal Co-IP and recombinant-domain binding assays showed CCp3 engages all six PfCCp members through direct adhesion-domain contacts.","evidence":"Co-immunoprecipitation from gametocyte lysates plus affinity chromatography co-elution with recombinant PfCCp domains and five gene-disruptant lines","pmids":["19304662"],"confidence":"High","gaps":["Precise CCp3 domains mediating each contact not fully mapped","The extracellular ligand or host target of the assembled complex unknown","Structural model of the complex not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Additional factors governing complex stability were probed; PfWLP1 knockdown reduced PfCCp1 and PfCCp2 levels, implicating a WD40 protein in maintaining the assembly that includes CCp3 — though the effect on CCp3 itself was not directly measured.","evidence":"Reverse-genetic knockdown of PfWLP1 with Western blot of PfCCp1/PfCCp2 and exflagellation assays","pmids":["35923798"],"confidence":"Low","gaps":["Effect on CCp3 protein not directly assayed — inference only","Single lab, indirect evidence for CCp3's dependence","Mechanism by which PfWLP1 stabilizes the complex unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The molecular ligand engaged by the CCp3-containing adhesion complex and the mechanistic basis for the salivary gland transition block remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No identified extracellular binding target of the complex","No structural model of CCp3 or the assembled complex","Causal link between complex loss and the transmission block not mechanistically defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfCCp multi-protein adhesion complex (all six PfCCp family members) [#3]"],"partners":["PFCCP1 (CO-DEPENDENT STABILIZATION) [#1, #3]","PFCCP2 (CO-DEPENDENT STABILIZATION) [#1, #3]","PFCCP4 / PFCCP5 / OTHER PFCCP MEMBERS (DIRECT ADHESION-DOMAIN BINDING) [#3]","PFWLP1 (WD40 PROTEIN REQUIRED FOR COMPLEX STABILITY; EFFECT SHOWN ON PFCCP1/PFCCP2) [#4]"],"other_free_text":["Sexual-stage-specific expression in mature gametocytes (stages II–V) and macrogametes; present on male and female gametocytes but absent from exflagellating microgametes [#0, #2].","Gene disruption permits oocyst sporozoite formation but blocks salivary gland transition, defining an essential role in mosquito-stage transmission [#0].","CCp3 loss destabilizes PfCCp1 and PfCCp2 protein without affecting their transcripts, indicating post-transcriptional co-dependence [#1]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15184503","id":"PMC_15184503","title":"A multidomain adhesion protein family expressed in Plasmodium falciparum is essential for transmission to the mosquito.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15184503","citation_count":104,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfCCp3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12354219","id":"PMC_12354219","title":"A malaria scavenger receptor-like protein essential for parasite development.","date":"2002","source":"Molecular 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parasites capable of forming oocyst sporozoites but blocked in salivary gland transition, establishing CCp3 as essential for mosquito-to-salivary-gland transmission.\",\n      \"method\": \"Targeted gene disruption by homologous recombination; transcript and protein expression analysis; cellular localization studies\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined transmission phenotype, replicated alongside sibling family members, localization confirmed by imaging\",\n      \"pmids\": [\"15184503\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Abrogation of CCp3 (PfCCp3) by gene disruption leads to loss of PfCCp1 and PfCCp2 protein but not their transcripts, demonstrating co-dependent protein expression and suggesting that CCp3 is required for the stability or formation of a multi-protein complex containing these three proteins.\",\n      \"method\": \"Targeted gene disruption; Western blot and RT-PCR analysis of co-dependent expression in gene-disruptant parasites\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with protein and mRNA level distinction, single lab, two orthogonal methods\",\n      \"pmids\": [\"16388802\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CCp3 (PfCCp3) is co-dependently expressed with PfCCp1 and PfCCp2 in the parasitophorous vacuole associated with the gametocyte plasma membrane (stages II–V), is present on both male and female gametocytes and macrogametes but absent from exflagellating microgametes, and targeted gene disruption of PfCCp3 inhibits parasite development in the mosquito vector.\",\n      \"method\": \"Immunofluorescence localization; stage-specific expression analysis; gene disruption phenotypic analysis; exflagellation assays with antibodies\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IFA, gene disruption, functional assays), confirms and extends earlier findings from a separate lab\",\n      \"pmids\": [\"17950739\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CCp3 (PfCCp3) participates in multi-protein complexes with all six PfCCp family members in gametocytes, as demonstrated by co-immunoprecipitation from gametocyte lysates and affinity chromatography co-elution binding assays with recombinant PfCCp domains showing direct binding between distinct adhesion domains.\",\n      \"method\": \"Co-immunoprecipitation from gametocyte lysates; affinity chromatography co-elution binding assays with recombinant PfCCp domains; five gene-disruptant parasite lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus affinity binding assays with recombinant domains, multiple gene-disruptant lines, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19304662\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of the WD40-repeat protein PfWLP1 in P. falciparum leads to reduced protein levels of PfCCp1 and PfCCp2 (key components of the PfCCp-based adhesion complex that includes CCp3), indicating that PfWLP1 is required for stability of the complex that contains CCp3 family members.\",\n      \"method\": \"Reverse genetics (knockdown); Western blot quantification of PfCCp1 and PfCCp2 levels; gametocyte exflagellation assays\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown phenotype is shown for PfCCp1 and PfCCp2, not directly for CCp3 itself; single lab, indirect evidence for CCp3's place in the complex\",\n      \"pmids\": [\"35923798\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"CCp3 (PF3D7_1407000) is a sexually-stage-specific, multi-domain adhesion protein expressed on the surface of gametocytes (stages II–V) and macrogametes in P. falciparum; it is a core member of a multi-protein complex formed by all six PfCCp family members in the parasitophorous vacuole, where the loss of CCp3 protein destabilizes PfCCp1 and PfCCp2 (co-dependent expression at the post-transcriptional level), and targeted disruption of the CCp3 gene blocks parasite development at the salivary gland transition step in the mosquito, establishing an essential role in mosquito-stage transmission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCp3 (PF3D7_1407000) is a sexual-stage adhesion protein of P. falciparum that is essential for parasite transmission through the mosquito vector [#0, #2]. It is expressed in mature gametocytes with plasma membrane-associated localization, is present in the parasitophorous vacuole associated with the gametocyte plasma membrane across stages II\\u2013V, and is found on both male and female gametocytes and on macrogametes but is absent from exflagellating microgametes [#0, #2]. CCp3 is a core member of a multi-protein adhesion complex that includes all six PfCCp family members, binding partner proteins through direct interactions between distinct adhesion domains [#3]. Within this complex, CCp3 has an architectural role: targeted disruption of the CCp3 gene abolishes PfCCp1 and PfCCp2 protein without affecting their transcripts, demonstrating co-dependent, post-transcriptional stabilization of complex members [#1]. Functionally, gene disruption permits oocyst sporozoite formation but blocks the salivary gland transition step, pinpointing CCp3 to a defined late mosquito-stage developmental transition [#0]. Beyond its membership in and stabilization of this PfCCp complex and its transmission phenotype, no further biochemical activity of CCp3 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing whether CCp3 has a non-redundant biological function required a genetic test; knockout defined it as essential for a specific mosquito-stage transition.\",\n      \"evidence\": \"Targeted gene disruption by homologous recombination with transcript, protein, and localization analysis in P. falciparum gametocytes\",\n      \"pmids\": [\"15184503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism underlying the salivary gland transition block not defined\", \"No biochemical activity assigned to the protein\", \"Binding partners not yet identified at this stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether CCp3 acts alone or as part of an interdependent assembly was unknown; loss of CCp3 collapsing PfCCp1 and PfCCp2 protein but not transcript revealed a post-transcriptional co-dependence indicative of a shared complex.\",\n      \"evidence\": \"Gene disruption with Western blot versus RT-PCR comparison in disruptant parasites\",\n      \"pmids\": [\"16388802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve direct versus indirect stabilization\", \"Single lab\", \"Stoichiometry and full complex membership not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The precise localization and cellular distribution of the co-dependent CCp assembly was refined, placing CCp3 in the gametocyte parathophorous vacuole at the plasma membrane across sexual stages and cell types.\",\n      \"evidence\": \"Immunofluorescence localization, stage-specific expression, exflagellation assays and gene disruption in P. falciparum\",\n      \"pmids\": [\"17950739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reason for absence from exflagellating microgametes unexplained\", \"Does not define the adhesion target of the complex\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether the co-dependence reflected direct physical interaction was untested; reciprocal Co-IP and recombinant-domain binding assays showed CCp3 engages all six PfCCp members through direct adhesion-domain contacts.\",\n      \"evidence\": \"Co-immunoprecipitation from gametocyte lysates plus affinity chromatography co-elution with recombinant PfCCp domains and five gene-disruptant lines\",\n      \"pmids\": [\"19304662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise CCp3 domains mediating each contact not fully mapped\", \"The extracellular ligand or host target of the assembled complex unknown\", \"Structural model of the complex not determined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Additional factors governing complex stability were probed; PfWLP1 knockdown reduced PfCCp1 and PfCCp2 levels, implicating a WD40 protein in maintaining the assembly that includes CCp3 \\u2014 though the effect on CCp3 itself was not directly measured.\",\n      \"evidence\": \"Reverse-genetic knockdown of PfWLP1 with Western blot of PfCCp1/PfCCp2 and exflagellation assays\",\n      \"pmids\": [\"35923798\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Effect on CCp3 protein not directly assayed \\u2014 inference only\", \"Single lab, indirect evidence for CCp3's dependence\", \"Mechanism by which PfWLP1 stabilizes the complex unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular ligand engaged by the CCp3-containing adhesion complex and the mechanistic basis for the salivary gland transition block remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No identified extracellular binding target of the complex\", \"No structural model of CCp3 or the assembled complex\", \"Causal link between complex loss and the transmission block not mechanistically defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0020003\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0090599\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"PfCCp multi-protein adhesion complex (all six PfCCp family members) [#3]\"\n    ],\n    \"partners\": [\n      \"PfCCp1 (co-dependent stabilization) [#1, #3]\",\n      \"PfCCp2 (co-dependent stabilization) [#1, #3]\",\n      \"PfCCp4 / PfCCp5 / other PfCCp members (direct adhesion-domain binding) [#3]\",\n      \"PfWLP1 (WD40 protein required for complex stability; effect shown on PfCCp1/PfCCp2) [#4]\"\n    ],\n    \"other_free_text\": [\n      \"Sexual-stage-specific expression in mature gametocytes (stages II\\u2013V) and macrogametes; present on male and female gametocytes but absent from exflagellating microgametes [#0, #2].\",\n      \"Gene disruption permits oocyst sporozoite formation but blocks salivary gland transition, defining an essential role in mosquito-stage transmission [#0].\",\n      \"CCp3 loss destabilizes PfCCp1 and PfCCp2 protein without affecting their transcripts, indicating post-transcriptional co-dependence [#1].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1407000","name":null,"product":"LCCL domain-containing protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1035200","name":null,"product":"LCCL domain-containing protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1351100","name":null,"product":"LCCL domain-containing protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CCp3","evaluation":null}