The PH domain in the ArfGAP ASAP1 drives catalytic activation through an unprecedented allosteric mechanism.

ABSTRACT: ASAP1 is a multidomain Arf GTPase-activating protein (ArfGAP) that catalyzes GTP hydrolysis on the small GTPase Arf1 and is implicated in cancer progression. The PH domain of ASAP1 enhances its activity greater than 7 orders of magnitude but the underlying mechanisms remain poorly understood. Here, we combined Nuclear Magnetic Resonance (NMR), Molecular Dynamic (MD) simulations and mathematical modeling of functional data to build a comprehensive structural-mechanistic model of the complex of Arf1 and the ASAP1 PH domain on a membrane surface. Our results support a new conceptual model in which the PH domain contributes to efficient catalysis not only by membrane recruitment but by acting as a critical component of the catalytic interface, binding Arf·GTP and allosterically driving it towa

SUBMITTER: Soubias O 

PROVIDER: S-EPMC11702723 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature