@article{a77e879af6ea4ffa85517986c45b67ef,
title = "Membrane surface recognition by the ASAP1 PH domain and consequences for interactions with the small GTPase Arf1",
abstract = "Adenosine diphosphate-ribosylation factor (Arf) guanosine triphosphatase-activating proteins (GAPs) are enzymes that need to bind to membranes to catalyze the hydrolysis of guanosine triphosphate (GTP) bound to the small GTP-binding protein Arf. Binding of the pleckstrin homology (PH) domain of the ArfGAP With SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) to membranes containing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is key for maximum GTP hydrolysis but not fully understood. By combining nuclear magnetic resonance, neutron reflectometry, and molecular dynamics simulation, we show that binding of multiple PI(4,5)P2 molecules to the ASAP1 PH domain (i) triggers a functionally relevant allosteric conformational switch and (ii) maintains the PH domain in a well-defined orientation, allowing critical contacts with an Arf1 mimic to occur. Our model provides a framework to understand how binding of the ASAP1 PH domain to PI(4,5)P2 at the membrane may play a role in the regulation of ASAP1.",
author = "Olivier Soubias and Shashank Pant and Frank Heinrich and Yue Zhang and Roy, {Neeladri Sekhar} and Jess Li and Xiaoying Jian and Yohe, {Marielle E.} and Randazzo, {Paul A.} and Mathias L{\"o}sche and Emad Tajkhorshid and Byrd, {R. Andrew}",
note = "Funding Information: We acknowledge the use of the Biophysics Resource, Structural Biophysics Laboratory, and the assistance of S. Tarasov and M. Dyba. Funding: O.S., Y.Z., J.L., and R.A.B. were supported by the Intramural Research Program of the National Cancer Institute, Projects ZIA BC 011419, ZIA BC 011131, and ZIA BC 011132. N.S.R., X.J., M.E.Y., and P.A.R. were supported by the Intramural Research Program of the National Cancer Institute, Project BC007365. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. F.H. and M.L. were supported by the U.S. Department of Commerce, Award 70NANB17H299. Research was performed, in part, at the National Institute of Standards and Technology (NIST) Center for Nanoscale Science and Technology. Certain commercial materials, equipment, and instruments are identified in this work to describe the experimental procedure as completely as possible. In no case does such an identification imply a recommendation or endorsement by NIST, nor does it imply that the materials, equipment, or instrument identified is necessarily the best available for the purpose. Portions of the research reported in this publication was supported by the NIH under award numbers P41-GM104601 (to E.T.) and R01-GM123455 (to E.T.). We also acknowledge computing resources provided by Blue Waters at the National Center for Super-computing Applications and Extreme Science and Engineering Discovery Environment (grant MCA06N060 to E.T.). S.P. would like to thank the Beckman Institute Graduate Fellowship for funding.",
year = "2020",
month = sep,
day = "30",
doi = "10.1126/sciadv.abd1882",
language = "English (US)",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "40",
}