O. Soubias, Shashank Pant, F. Heinrich, N. S. Roy Y. Zhang, J. Li, X. Jian,
M. E Yohe, P. A. Randazzo, M. Lösche, Emad Tajkhorshid, and R. A. Byrd.
Membrane surface recognition by the ASAP1 PH domain and
consequences for interactions with the small GTPase Arf1.
Science Advances, 6, 2020.
(PMC: PMC7527224)
SOUB2020-ET
ADP-ribosylation factor (Arf) GTPase-activating proteins (GAPs) are enzymes
that need to bind to membranes to catalyze the hydrolysis of GTP bound to the
small GTP-binding protein Arf and terminate signaling. Binding of the PH
domain of the ArfGAP ASAP1 to membranes containing the phosphatidylinositol
phosphate PIP(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
to the ASAP1 Pleckstrin homology (PH) domain (i) triggers a functionally
relevant allosteric conformational switch involving regions distant from the
membrane interface, and (ii) maintains the PH domain in a well-defined
orientation, allowing critical contacts between the newly exposed segments and
an Arf1 mimic to occur. Our model provides a framework to understand how the
interaction between PI(4,5)P2 and the ASAP1 PH domain at the membrane may
play a role in the regulation of ASAP1.
