IMC1h

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.

1. 2010 High

   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

   PMID:21098480

   Open questions at the time

   • 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
2. 2012 High

   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

   PMID:22844474

   Open questions at the time

   • 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
3. 2019 High

   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

   PMID:31428588

   Open questions at the time

   • 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

• The molecular partners through which IMC1h links the membrane skeleton to the gliding apparatus, and its function in human-infective Plasmodium species, remain undefined.
• 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