{"gene":"PF3D7_1221400","run_date":"2026-09-08T16:55:26+00:00","timeline":{"discoveries":[{"year":2010,"finding":"IMC1h localizes to the pellicle of both ookinetes and sporozoites in Plasmodium berghei, and knock-out of IMC1h reduces ookinete strength, motility, and infectivity, mimicking loss of IMC1a and IMC1b in their respective stages. Double knock-out of IMC1h and IMC1b exacerbated single knock-out phenotypes in ookinete strength, motility, and infectivity without further affecting ookinete morphology, providing genetic evidence that IMC1h contributes to gliding motility independently of cell shape and that IMC1 proteins operate independently of each other.","method":"Subcellular localization by direct imaging; single and double knock-out (loss-of-function) with phenotypic readouts of cell morphology, tensile strength, motility, and infectivity; genetic epistasis via double null mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis with double KO plus multiple orthogonal phenotypic readouts (morphology, strength, motility, infectivity) with direct localization data","pmids":["21098480"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2012,"finding":"Deletion of IMC1h (PBANKA_143660) in Plasmodium berghei impairs directionality and motility behaviour of both ookinetes and sporozoites. IMC1h-null sporozoites can invade mosquito salivary glands but fail to progress normally through the mammalian dermis in vivo. Colocalization of IMC1h with residual IMC was detected in liver stages up to 30 hours post-infection; parasites lacking IMC1h showed developmental defects in liver stages in vitro and delayed blood-stage infection in vivo, indicating IMC1h maintains cellular architecture supporting motility, dermal transit, and liver-stage development.","method":"Time-lapse live imaging of motility directionality and behaviour; gene deletion (knock-out) with in vivo dermis traversal assay, salivary gland invasion assay, hepatoma cell transmigration/invasion assay, in vitro liver-stage development assay, and in vivo blood-stage patency; colocalization imaging of IMC1h with IMC marker in liver stages","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal in vivo and in vitro assays and direct colocalization; replicated finding on motility from independent lab","pmids":["22844474"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":"PBANKA_143660 locus"}]},{"year":2019,"finding":"Structure-function analysis using allelic replacement in Plasmodium berghei demonstrated that the alveolin domain of IMC1h is responsible for targeting the protein to the membrane skeleton; deletion of the alveolin domain abolishes correct localization and results in loss of function (abnormal zoite shape, reduced tensile strength, motility, and infectivity). The non-alveolin conserved domain is dispensable for membrane-skeleton targeting and tensile strength but is required for motility, indicating that tensile strength and locomotion are mechanistically uncoupled and that the non-alveolin domain may engage with the locomotion apparatus.","method":"Allelic replacement (domain deletion) in Plasmodium berghei; subcellular localization of domain-deletion variants; tensile strength assay; motility assay; infectivity assay","journal":"Frontiers in cellular and infection microbiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain-resolution structure-function via allelic replacement with multiple orthogonal functional readouts (localization, strength, motility, infectivity) in a single rigorous study","pmids":["31428588"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"IMC1h (PF3D7_1221400) is an alveolin/IMC protein whose alveolin domain targets it to the subpellicular membrane skeleton of Plasmodium berghei ookinetes and sporozoites, where it contributes independently of other IMC1 family members to maintaining cellular architecture, tensile strength, and—via its distinct non-alveolin conserved domain—gliding motility (uncoupled from tensile strength), and is additionally required for liver-stage development and productive colonisation of the mammalian host."},"narrative":{"mechanistic_narrative":"IMC1h (PF3D7_1221400) is an alveolin-family protein of the inner membrane complex that localizes to the pellicle/subpellicular membrane skeleton of Plasmodium berghei ookinetes and sporozoites, where it maintains the cellular architecture underpinning tensile strength, gliding motility, and host infectivity [PMID:21098480, PMID:22844474]. Loss-of-function studies establish that IMC1h contributes to gliding motility independently of cell shape, and epistasis with IMC1b shows that IMC1 family members act independently of one another rather than redundantly [PMID:21098480]. Structure-function dissection assigns two separable roles to distinct domains: the alveolin domain targets IMC1h to the membrane skeleton and is required for tensile strength, whereas a distinct non-alveolin conserved domain is dispensable for skeletal targeting and strength but required for motility, mechanistically uncoupling tensile strength from locomotion [PMID:31428588]. Beyond its structural role, IMC1h is required for directional motility, transit through the mammalian dermis, liver-stage development, and timely blood-stage patency, linking membrane-skeleton integrity to productive colonization of the mammalian host [PMID:22844474]. All available evidence derives from the P. berghei ortholog; no biochemical binding partners of IMC1h have been characterized in the available corpus.","teleology":[{"year":2010,"claim":"To determine whether IMC1h has a stage-specific structural role, its pellicle localization and the consequences of its loss were tested, establishing that it independently supports strength, motility, and infectivity across ookinetes and sporozoites.","evidence":"Direct imaging localization plus single and double (IMC1h/IMC1b) knock-outs with morphology, tensile strength, motility, and infectivity readouts in P. berghei","pmids":["21098480"],"confidence":"High","gaps":["No biochemical partners or molecular link between IMC1h and the motility machinery identified","Independence from IMC1b shown genetically but the physical basis of non-redundancy unknown","Findings limited to P. berghei; human-infective ortholog untested"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2012,"claim":"To assess where IMC1h matters during transmission, deletion phenotypes were traced through mosquito, dermal, and liver stages, showing the protein sustains directional motility, dermal transit, and liver-stage development rather than acting at a single step.","evidence":"Time-lapse motility imaging plus KO with in vivo dermis traversal, salivary gland invasion, hepatoma transmigration, in vitro liver-stage development assays, in vivo blood-stage patency, and liver-stage colocalization with an IMC marker in P. berghei","pmids":["22844474"],"confidence":"High","gaps":["Colocalization with IMC marker does not establish direct molecular interaction","Mechanism by which IMC1h loss delays blood-stage patency unresolved","Whether the liver-stage defect is architectural or signaling in origin unknown"],"attribution":[{"species":"Plasmodium berghei","strain":"PBANKA_143660 locus"}]},{"year":2019,"claim":"To resolve which parts of IMC1h drive its distinct functions, domain-deletion allelic replacements separated the alveolin domain (targeting and tensile strength) from the non-alveolin conserved domain (motility), showing strength and locomotion are mechanistically uncoupled.","evidence":"Allelic replacement domain deletions in P. berghei with localization, tensile strength, motility, and infectivity assays","pmids":["31428588"],"confidence":"High","gaps":["The proposed engagement of the non-alveolin domain with the locomotion apparatus not demonstrated biochemically","No structural model of either domain","Interacting proteins recruited by either domain unidentified"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The molecular partners through which IMC1h links the membrane skeleton to the gliding apparatus, and its function in human-infective Plasmodium species, remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No physical interactors of IMC1h identified in any species","No direct characterization of PF3D7_1221400 in P. falciparum; all functional data are from the P. berghei ortholog","Structural basis of alveolin-domain membrane-skeleton targeting unresolved"],"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Inner membrane complex / subpellicular membrane skeleton (alveolin network)"],"partners":[],"other_free_text":["Alveolin domain mediates membrane-skeleton targeting and tensile strength; a distinct non-alveolin conserved domain is required for motility, uncoupling strength from locomotion [#2]","Acts independently of IMC1b (non-redundant IMC1 family members) as shown by double knock-out epistasis [#0]","Required for directional motility, mammalian dermal transit, liver-stage development, and timely blood-stage patency in P. berghei [#1]","All functional evidence is from the P. berghei ortholog (PBANKA_143660); PF3D7_1221400 itself is inferred by orthology"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"22844474","id":"PMC_22844474","title":"The alveolin IMC1h is required for normal ookinete and sporozoite motility behaviour and host colonisation in Plasmodium berghei.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22844474","citation_count":55,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["IMC1h"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21098480","id":"PMC_21098480","title":"Malaria IMC1 membrane skeleton proteins operate autonomously and participate in motility independently of cell shape.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21098480","citation_count":44,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["IMC1h"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31428588","id":"PMC_31428588","title":"Distinct Functional Contributions by the Conserved Domains of the Malaria Parasite Alveolin IMC1h.","date":"2019","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31428588","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["IMC1h"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4273,"output_tokens":1245,"usd":0.015747,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6126,"output_tokens":2164,"usd":0.042365,"stage2_stop_reason":"end_turn"},"total_usd":0.0,"stage1_batch_id":"msgbatch_01BW7vvc7h5iV39oJ1MHMzXw","stage2_batch_id":"msgbatch_01Kh5HbgbPXepNfNCbktYkSD","note":"batch pricing = 50% of standard","skipped":true},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"IMC1h localizes to the pellicle of both ookinetes and sporozoites in Plasmodium berghei, and knock-out of IMC1h reduces ookinete strength, motility, and infectivity, mimicking loss of IMC1a and IMC1b in their respective stages. Double knock-out of IMC1h and IMC1b exacerbated single knock-out phenotypes in ookinete strength, motility, and infectivity without further affecting ookinete morphology, providing genetic evidence that IMC1h contributes to gliding motility independently of cell shape and that IMC1 proteins operate independently of each other.\",\n      \"method\": \"Subcellular localization by direct imaging; single and double knock-out (loss-of-function) with phenotypic readouts of cell morphology, tensile strength, motility, and infectivity; genetic epistasis via double null mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis with double KO plus multiple orthogonal phenotypic readouts (morphology, strength, motility, infectivity) with direct localization data\",\n      \"pmids\": [\"21098480\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Deletion of IMC1h (PBANKA_143660) in Plasmodium berghei impairs directionality and motility behaviour of both ookinetes and sporozoites. IMC1h-null sporozoites can invade mosquito salivary glands but fail to progress normally through the mammalian dermis in vivo. Colocalization of IMC1h with residual IMC was detected in liver stages up to 30 hours post-infection; parasites lacking IMC1h showed developmental defects in liver stages in vitro and delayed blood-stage infection in vivo, indicating IMC1h maintains cellular architecture supporting motility, dermal transit, and liver-stage development.\",\n      \"method\": \"Time-lapse live imaging of motility directionality and behaviour; gene deletion (knock-out) with in vivo dermis traversal assay, salivary gland invasion assay, hepatoma cell transmigration/invasion assay, in vitro liver-stage development assay, and in vivo blood-stage patency; colocalization imaging of IMC1h with IMC marker in liver stages\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal in vivo and in vitro assays and direct colocalization; replicated finding on motility from independent lab\",\n      \"pmids\": [\"22844474\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"PBANKA_143660 locus\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structure-function analysis using allelic replacement in Plasmodium berghei demonstrated that the alveolin domain of IMC1h is responsible for targeting the protein to the membrane skeleton; deletion of the alveolin domain abolishes correct localization and results in loss of function (abnormal zoite shape, reduced tensile strength, motility, and infectivity). The non-alveolin conserved domain is dispensable for membrane-skeleton targeting and tensile strength but is required for motility, indicating that tensile strength and locomotion are mechanistically uncoupled and that the non-alveolin domain may engage with the locomotion apparatus.\",\n      \"method\": \"Allelic replacement (domain deletion) in Plasmodium berghei; subcellular localization of domain-deletion variants; tensile strength assay; motility assay; infectivity assay\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-resolution structure-function via allelic replacement with multiple orthogonal functional readouts (localization, strength, motility, infectivity) in a single rigorous study\",\n      \"pmids\": [\"31428588\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"IMC1h (PF3D7_1221400) is an alveolin/IMC protein whose alveolin domain targets it to the subpellicular membrane skeleton of Plasmodium berghei ookinetes and sporozoites, where it contributes independently of other IMC1 family members to maintaining cellular architecture, tensile strength, and—via its distinct non-alveolin conserved domain—gliding motility (uncoupled from tensile strength), and is additionally required for liver-stage development and productive colonisation of the mammalian host.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IMC1h (PF3D7_1221400) is an alveolin-family protein of the inner membrane complex that localizes to the pellicle/subpellicular membrane skeleton of Plasmodium berghei ookinetes and sporozoites, where it maintains the cellular architecture underpinning tensile strength, gliding motility, and host infectivity [#0, #1]. Loss-of-function studies establish that IMC1h contributes to gliding motility independently of cell shape, and epistasis with IMC1b shows that IMC1 family members act independently of one another rather than redundantly [#0]. Structure-function dissection assigns two separable roles to distinct domains: the alveolin domain targets IMC1h to the membrane skeleton and is required for tensile strength, whereas a distinct non-alveolin conserved domain is dispensable for skeletal targeting and strength but required for motility, mechanistically uncoupling tensile strength from locomotion [#2]. Beyond its structural role, IMC1h is required for directional motility, transit through the mammalian dermis, liver-stage development, and timely blood-stage patency, linking membrane-skeleton integrity to productive colonization of the mammalian host [#1]. All available evidence derives from the P. berghei ortholog; no biochemical binding partners of IMC1h have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"To determine whether IMC1h has a stage-specific structural role, its pellicle localization and the consequences of its loss were tested, establishing that it independently supports strength, motility, and infectivity across ookinetes and sporozoites.\",\n      \"evidence\": \"Direct imaging localization plus single and double (IMC1h/IMC1b) knock-outs with morphology, tensile strength, motility, and infectivity readouts in P. berghei\",\n      \"pmids\": [\"21098480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No biochemical partners or molecular link between IMC1h and the motility machinery identified\",\n        \"Independence from IMC1b shown genetically but the physical basis of non-redundancy unknown\",\n        \"Findings limited to P. berghei; human-infective ortholog untested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To assess where IMC1h matters during transmission, deletion phenotypes were traced through mosquito, dermal, and liver stages, showing the protein sustains directional motility, dermal transit, and liver-stage development rather than acting at a single step.\",\n      \"evidence\": \"Time-lapse motility imaging plus KO with in vivo dermis traversal, salivary gland invasion, hepatoma transmigration, in vitro liver-stage development assays, in vivo blood-stage patency, and liver-stage colocalization with an IMC marker in P. berghei\",\n      \"pmids\": [\"22844474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Colocalization with IMC marker does not establish direct molecular interaction\",\n        \"Mechanism by which IMC1h loss delays blood-stage patency unresolved\",\n        \"Whether the liver-stage defect is architectural or signaling in origin unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"PBANKA_143660 locus\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To resolve which parts of IMC1h drive its distinct functions, domain-deletion allelic replacements separated the alveolin domain (targeting and tensile strength) from the non-alveolin conserved domain (motility), showing strength and locomotion are mechanistically uncoupled.\",\n      \"evidence\": \"Allelic replacement domain deletions in P. berghei with localization, tensile strength, motility, and infectivity assays\",\n      \"pmids\": [\"31428588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The proposed engagement of the non-alveolin domain with the locomotion apparatus not demonstrated biochemically\",\n        \"No structural model of either domain\",\n        \"Interacting proteins recruited by either domain unidentified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular partners through which IMC1h links the membrane skeleton to the gliding apparatus, and its function in human-infective Plasmodium species, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No physical interactors of IMC1h identified in any species\",\n        \"No direct characterization of PF3D7_1221400 in P. falciparum; all functional data are from the P. berghei ortholog\",\n        \"Structural basis of alveolin-domain membrane-skeleton targeting unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0070258\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071976\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"Inner membrane complex / subpellicular membrane skeleton (alveolin network)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Alveolin domain mediates membrane-skeleton targeting and tensile strength; a distinct non-alveolin conserved domain is required for motility, uncoupling strength from locomotion [#2]\",\n      \"Acts independently of IMC1b (non-redundant IMC1 family members) as shown by double knock-out epistasis [#0]\",\n      \"Required for directional motility, mammalian dermal transit, liver-stage development, and timely blood-stage patency in P. berghei [#1]\",\n      \"All functional evidence is from the P. berghei ortholog (PBANKA_143660); PF3D7_1221400 itself is inferred by orthology\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1221400","name":null,"product":"inner membrane complex protein 1h, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1436600","name":null,"product":"inner membrane complex protein 1h","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1440500","name":null,"product":"inner membrane complex protein 1h, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"IMC1h","evaluation":null}