GAC

GAC (PF3D7_1361800) is a conserved apical connector protein of apicomplexan invasive stages that physically couples extracellular adhesion to the intracellular actomyosin motor to drive gliding motility, host cell invasion, and egress (PMID:27978434). Characterized in the Toxoplasma gondii and Plasmodium berghei orthologs, GAC binds and stabilizes filamentous actin through its N-terminal armadillo domain, engages the cytoplasmic tail of the micronemal transmembrane adhesin TgMIC2, and anchors to membranes through PH-domain recognition of phosphatidic acid, with its apical positioning depending on the lysine methyltransferase TgAKMT (PMID:27978434). In P. berghei, the ortholog concentrates at the extreme apical tip of the merozoite, binds the erythrocyte surface in a heparan sulfate-dependent manner, associates by IP-MS with multiple secreted invasion proteins, and is a target of invasion-inhibitory antibodies (PMID:41152982). No direct experimental characterization of the P. falciparum PF3D7_1361800 protein itself is present in the corpus beyond a structural inference that it bridges actin filaments to the plasma membrane within the geometrically constrained sub-pellicular compartment (PMID:35377914).

1. 2016 High

   Established the founding molecular function of GAC: how does extracellular adhesion transmit force to the intracellular motor? GAC was shown to be the physical bridge linking micronemal adhesins to actomyosin.

   Evidence Co-IP, actin- and lipid-binding assays, localization, and conditional knockout with gliding/invasion/egress readouts in T. gondii and P. berghei

   PMID:27978434

   Open questions at the time

   • No direct experiment on the P. falciparum PF3D7_1361800 ortholog
   • Structural basis of simultaneous actin, adhesin-tail, and phosphatidic acid engagement not resolved
   • Mechanism by which TgAKMT controls apical positioning undefined
2. 2022 Low

   Addressed how GAC fits within the crowded sub-pellicular space: structural modeling of the P. falciparum glideosome inferred that GAC's elongated dimensions bridge actin to the plasma membrane and constrain motor geometry.

   Evidence Cryo-EM of the PfActomyosin complex with dimensional modeling of GAC cited from prior biophysical data; no direct experiment on GAC performed

   PMID:35377914

   Open questions at the time

   • Inference only — no direct structural or functional experiment on PF3D7_1361800 was performed in this study
   • GAC's geometry within the assembled glideosome not directly visualized
   • Whether P. falciparum GAC behaves as the orthologs do is not tested
3. 2025 Medium

   Extended GAC's role beyond the intracellular motor connector: does GAC also directly contact the host cell? The P. berghei ortholog was shown to bind the erythrocyte surface via heparan sulfate and to be an invasion-inhibitory antibody target.

   Evidence Western blot, IFA, flow cytometry, heparinase II and heparin-sepharose binding assays, IP-MS, and passive immunization invasion-inhibition in murine models

   PMID:41152982

   Open questions at the time

   • Single-lab study; replication not yet established
   • Direct host-parasite binding partner of GAC on the erythrocyte not identified
   • Whether apparent apical-surface exposure reflects genuine extracellular display versus co-purified secreted proteins is unresolved

• Whether the P. falciparum PF3D7_1361800 protein directly recapitulates the actin-binding, adhesin-linking, and lipid-anchoring activities defined in orthologs, and whether it engages host-cell ligands, remains experimentally unaddressed in this corpus.
• No direct biochemical or genetic characterization of PF3D7_1361800 itself
• No structural model of the P. falciparum protein
• Host-cell binding shown only for the P. berghei ortholog