GAC

GAC (glideosome-associated connector) is an apical armadillo/PH domain protein that mechanically couples the actomyosin motor to surface adhesins to power gliding motility, host-cell invasion, and egress in apicomplexan parasites (PMID:27978434). It binds and stabilizes filamentous actin and physically bridges F-actin to the micronemal transmembrane adhesin TgMIC2, thereby transmitting myosin-generated force to the substrate; genetic disruption of GAC abolishes motility, invasion, and egress (PMID:27978434). GAC acts downstream of actin polymerization rather than in its initiation: FRM1-driven F-actin flux persists in GAC-null parasites, defining GAC as the connector that engages this flux with adhesins rather than the source of the flux (PMID:30753127). Its PH domain recognizes phosphatidic acid, a lipid signal linked to microneme exocytosis, positioning GAC as a lipid sensor that coordinates the motor-adhesin coupling with invasion signaling (PMID:27978434). Structurally, GAC is built from a supercoiled armadillo repeat region that crystallizes as a closed ring but can transition through open and extended conformations bearing distinct membrane- and F-actin-binding interfaces, providing a conformational basis for its bridging function (PMID:37014051). In Toxoplasma gondii, GAC is concentrated at the apical pole of invasive stages, and this positioning requires the apical lysine methyltransferase TgAKMT (PMID:27978434).

1. 2016 High

   Established GAC as the physical connector coupling surface adhesins to the actomyosin motor, answering how force is transmitted from the internal motor to the substrate during gliding.

   Evidence Co-immunoprecipitation, pulldown, and F-actin binding assays with genetic disruption scoring motility, invasion, and egress in Toxoplasma and Plasmodium

   PMID:27978434

   Open questions at the time

   • Structural basis of the actin- and adhesin-binding interfaces not resolved
   • Stoichiometry and dynamics of the connector complex undefined
2. 2016 High

   Defined how GAC is spatially restricted to the site of invasion by identifying TgAKMT as the regulator of its apical positioning.

   Evidence Immunofluorescence localization and TgAKMT genetic disruption assessing GAC mislocalization in Toxoplasma gondii

   PMID:27978434

   Open questions at the time

   • Whether TgAKMT methylates GAC directly is not shown
   • Molecular mechanism linking methylation to apical anchoring unknown
3. 2016 Medium

   Suggested GAC integrates a lipid signal into invasion by showing its PH domain binds phosphatidic acid, a mediator of microneme exocytosis.

   Evidence Lipid-binding assay of the isolated PH domain

   PMID:27978434

   Open questions at the time

   • Single lipid-binding assay from one lab
   • Functional consequence of PH-lipid binding for invasion not directly tested
4. 2019 Medium

   Placed GAC downstream of actin polymerization by showing FRM1-driven F-actin flux persists without GAC, distinguishing the connector role from flux initiation.

   Evidence F-actin chromobody live imaging combined with GAC gene disruption in Toxoplasma gondii

   PMID:30753127

   Open questions at the time

   • Live-imaging chromobody negative result from a single lab
   • How GAC engages flowing actin to transmit force not resolved
5. 2023 High

   Provided a conformational framework for GAC's bridging activity by resolving its supercoiled armadillo repeat ring and its capacity to adopt open/extended states with distinct binding interfaces.

   Evidence X-ray crystallography, SAXS/SEC solution biophysics, and F-actin/membrane binding interface mapping in Toxoplasma gondii

   PMID:37014051

   Open questions at the time

   • Trigger and timing of the closed-to-open transition in vivo unknown
   • Structure of GAC bound simultaneously to actin, membrane, and MIC2 not determined

• How GAC's conformational transitions, lipid sensing, and TgAKMT-dependent apical positioning are coordinated in time to trigger force transmission during invasion remains unresolved.
• No integrated model linking PH-domain lipid binding to conformational opening
• Direct substrate relationship between TgAKMT and GAC untested