Intrinsic GTP hydrolysis is observed for a switch 1 variant of Cdc42 in the presence of a specific GTPase inhibitor

Small GTPases
Kyla M MorrisPaul D Adams

Abstract

The Ras-related protein Cell division cycle 42 (Cdc42) is important in cell-signaling processes. Protein interactions involving Cdc42 occur primarily in flexible "Switch" regions that help regulate effector binding. We studied the kinetics of intrinsic GTP hydrolysis reaction in the absence and presence of a biologically active peptide derivative of a p21-activated kinase effector (PBD46) for wt Cdc42 and compared it to the Switch 1 variant Cdc42(T35A). While the binding of PBD46 to wt Cdc42 results in complete inhibition of GTP hydrolysis, this interaction in Cdc42(T35A) does not. Comparison of the crystal structure of wt Cdc42 in the absence of effector (1AN0.pdb), as well as the NMR structure of wt Cdc42 bound to an effector in the Switch 1 region (1CF4.pdb) ( www.rcsb.org ) suggests that the orientation of T(35) with bound Mg(2+) changes in the presence of effector, resulting in movement of GTP away from the catalytic box leading to the inhibition of GTP hydrolysis. For Cdc42(T35A), molecular dynamics simulations and structural analyses suggest that the nucleotide does not undergo the conformational shift observed for the wt Cdc42-effector interaction. Our data suggest that change in dynamics in the Switch 1 region of Cdc42...Continue Reading

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Citations

Sep 16, 2016·Small GTPases·Raquel B Haga, Anne J Ridley
Mar 29, 2014·Trends in Cell Biology·Tobias WelzEugen Kerkhoff
Nov 15, 2016·Expert Review of Anticancer Therapy·Nisha Durand, Peter Storz
Jan 6, 2017·Small GTPases·Matthias P Müller, Roger S Goody
Jan 27, 2017·Small GTPases·Guansong WangGuangyu Wu
Dec 15, 2017·Small GTPases·Marcellus J Banworth, Guangpu Li
Aug 10, 2018·Cytoskeleton·Julian David BaurThomas Gronemeyer
Jan 15, 2019·PloS One·Dieter WaschbüschAngelika Barnekow
Dec 22, 2020·Biophysical Journal·Nurit HaspelRuth Nussinov

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Methods Mentioned

BETA
GTPases
GTPase
NMR

Software Mentioned

PyMol
VMD
NAMD

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