An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function

Olivier Soubias, Samuel L. Foley, Xiaoying Jian, Rebekah A. Jackson, Yue Zhang, Eric M. Rosenberg, Benjamin J. Hu, Jess Li, Frank Heinrich, Margaret E. Johnson, Alexander J. Sodt, Paul A. Randazzo () and R. Andrew Byrd ()
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Olivier Soubias: National Institutes of Health
Samuel L. Foley: The Johns Hopkins University
Xiaoying Jian: National Institutes of Health
Rebekah A. Jackson: National Institutes of Health
Yue Zhang: National Institutes of Health
Eric M. Rosenberg: National Institutes of Health
Benjamin J. Hu: National Institutes of Health
Jess Li: National Institutes of Health
Frank Heinrich: Department of Physics Carnegie Mellon University
Margaret E. Johnson: The Johns Hopkins University
Alexander J. Sodt: National Institutes of Health
Paul A. Randazzo: National Institutes of Health
R. Andrew Byrd: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63764-w

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