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An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function
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An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function
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Journal Article
An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function
2025
Overview
GTPase-activating proteins are important regulators of small GTPases; among these, ASAP1 stimulates GTP hydrolysis on Arf1 and is implicated in cancer progression. ASAP1 contains a Pleckstrin Homology (PH) domain essential for maximum Arf·GTP hydrolysis. The prevailing view of PH domains is that they regulate proteins through passive mechanisms like membrane recruitment. In sharp contrast, we show that the PH domain of ASAP1 actively contributes to Arf1 GTP hydrolysis. By combining NMR, molecular dynamics simulations, kinetic assays, and mutational analysis, we find that the PH domain binds Arf·GTP at the membrane, to establish an active state primed for GTP hydrolysis. We identify key residues on the PH domain and Arf that drive this allosteric mechanism, which mathematical modeling shows contributes as much to GTPase activation as membrane recruitment. The finding that PH domains directly modulate small GTPases has broad implications for the Ras and Rho oncoprotein families.
GTPase-activating proteins (GAPs) often contain regulatory PH domains. In this work, Soubias et al, using an integrated structure-function approach, discovered a mechanism where a GAP PH domain binds directly to a GTPase to induce allosteric changes facilitating GTP hydrolysis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 119/118
/ 82/16
/ 82/58
/ 82/80
/ 82/83
/ Adaptor Proteins, Signal Transducing - chemistry
/ Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ ADP-Ribosylation Factor 1 - chemistry
/ ADP-Ribosylation Factor 1 - genetics
/ ADP-Ribosylation Factor 1 - metabolism
/ Guanosine Triphosphate - metabolism
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Kinetics
/ Molecular Dynamics Simulation
/ NMR
/ Proteins
/ Science
