GAPM2

GAPM2 (PF3D7_0423500) is a six-pass transmembrane protein of the Plasmodium falciparum inner membrane complex (IMC) that functions as an anchoring component linking the IMC membrane to the underlying cytoskeleton and motor machinery (PMID:19561073). It forms highly SDS-resistant oligomeric complexes and co-purifies with cytoskeletal alveolin proteins and, in part, with the actin-myosin motor, and it assembles into a heteromeric complex together with related six-pass transmembrane proteins in merozoites (PMID:19561073, PMID:19465059). GAPM2 additionally belongs to a PhIL1-associated complex that co-exists with the glideosome motor in the IMC (PMID:34324609). Functionally, conditional depletion of GAPM2 abolishes merozoite reorientation and gliding after the parasite has attached to the red blood cell, thereby blocking host cell invasion while leaving initial RBC attachment intact (PMID:34324609). Beyond this IMC-anchoring and invasion role, no further mechanistic detail on GAPM2 has been characterized in the available corpus.

1. 2009 Medium

   Establishing where GAPM2 resides and what it associates with was the first step in assigning it a structural role: it was shown to be an IMC-localized six-pass transmembrane protein forming SDS-resistant complexes with cytoskeletal alveolins and the actin-myosin motor, implicating it in anchoring the IMC to the subpellicular cytoskeleton.

   Evidence Subcellular fractionation, SDS-resistant complex analysis by SDS-PAGE/Western, and co-purification with cytoskeletal and motor components in P. falciparum

   PMID:19561073

   Open questions at the time

   • Anchoring role inferred from co-purification, not from loss-of-function or reconstitution
   • Direct binding partners within the SDS-resistant complex not resolved
   • Stoichiometry and architecture of the oligomeric complex unknown
2. 2009 Medium

   To test whether GAPM2 acts alone or within a defined assembly, it was shown to co-assemble with two related six-pass transmembrane proteins into a heteromeric IMC complex in merozoites, defining it as a member of an oligomeric membrane platform rather than an isolated protein.

   Evidence Immunofluorescence colocalization, reciprocal immunoprecipitation, baculovirus/insect-cell expression, and liposome reconstitution in P. falciparum

   PMID:19465059

   Open questions at the time

   • Identity of GAPM2-specific contributions versus its paralogous partners not separated
   • Functional consequence of heteromeric assembly not tested
   • Whether complex assembly requires the reconstituted membrane environment in vivo unknown
3. 2021 High

   The functional requirement for GAPM2 was resolved by conditional depletion, which showed that GAPM2 is part of a PhIL1-associated complex coexisting with the glideosome and is specifically required for merozoite reorientation and gliding after attachment, thereby defining its stage in the invasion sequence.

   Evidence Conditional knockdown/knockout with invasion, gliding, and reorientation assays plus immunofluorescence in P. falciparum

   PMID:34324609

   Open questions at the time

   • Molecular mechanism coupling GAPM2 to motor-driven reorientation not defined
   • Whether GAPM2 loss disrupts overall IMC/cytoskeleton integrity or acts more selectively unclear
   • Direct interaction between GAPM2 and PhIL1 versus indirect complex membership not distinguished

• How GAPM2 mechanically transmits force from the actin-myosin motor to the IMC membrane to drive reorientation and gliding, and which direct partners mediate this coupling, remains unresolved.
• No structural model of GAPM2 or its complexes
• Direct binding partners and force-transmission mechanism undefined
• Role, if any, in other life-cycle stages beyond merozoite invasion untested