Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

CDC42 binds PAK4 via an extended GTPase-effector interface

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2]
  1. Yale Univ. School of Medicine, New Haven, CT (United States)
  2. Yale Univ. School of Medicine, New Haven, CT (United States); Yale Univ., New Haven, CT (United States)
+ Show Author Affiliations
The p21-activated kinase (PAK) group of serine/threonine kinases are downstream effectors of RHO GTPases and play important roles in regulation of the actin cytoskeleton, cell growth, survival, polarity, and development. Here we probe the interaction of the type II PAK, PAK4, with RHO GTPases. Using solution scattering we find that the full-length PAK4 heterodimer with CDC42 adopts primarily a compact organization. Furthermore, X-ray crystallography reveals the molecular nature of the interaction between PAK4 and CDC42 and shows that in addition to the canonical PAK4 CDC42/RAC interactive binding (CRIB) domain binding to CDC42 there are unexpected contacts involving the PAK4 kinase C-lobe, CDC42, and the PAK4 polybasic region. These additional interactions modulate kinase activity and increase the binding affinity of CDC42 for full-length PAK4 compared with the CRIB domain alone. We therefore show that the interaction of CDC42 with PAK4 can influence kinase activity in a previously unappreciated manner.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institute of General Medical Sciences; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Grant/Contract Number:
SC0012704
OSTI ID:
1432871
Alternate ID(s):
OSTI ID: 1499537
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 3 Vol. 115; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (52)

Characterizing flexible and intrinsically unstructured biological macromolecules by SAS using the Porod-Debye law journal April 2011
NMRPipe: A multidimensional spectral processing system based on UNIX pipes journal November 1995
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Pak1 Kinase Homodimers Are Autoinhibited in trans and Dissociated upon Activation by Cdc42 and Rac1 journal January 2002
Multiple Rho proteins regulate the subcellular targeting of PAK5 journal December 2006
NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different from that of PAK1 journal August 2013
The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site journal August 2009
Structure, biochemistry, and biology of PAK kinases journal March 2017
Inference of Macromolecular Assemblies from Crystalline State journal September 2007
NADPH oxidase activator p67phox behaves in solution as a multidomain protein with semi-flexible linkers journal January 2010
UnPAKing the class differences among p21-activated kinases journal August 2008
Structural Characterization of Flexible Proteins Using Small-Angle X-ray Scattering journal May 2007
Structure of Cdc42 bound to the GTPase binding domain of PAK journal May 2000
Group I and II mammalian PAKs have different modes of activation by Cdc42 journal June 2012
PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas journal September 2017
Data publication with the structural biology data grid supports live analysis journal March 2016
An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1 journal November 2015
Regulation of RAF protein kinases in ERK signalling journal April 2015
Cloning and characterization of PAK5, a novel member of mammalianp21-activated kinase-II subfamily that is predominantly expressed in brain journal May 2002
A tale of two Paks journal February 2008
PAK5 is auto-activated by a central domain that promotes kinase oligomerization journal June 2016
Rho GTPases and their effector proteins journal May 2000
Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate journal September 2012
Structural Insights into the Interaction of ROCKI with the Switch Regions of RhoA journal December 2003
Signaling, Regulation, and Specificity of the Type II p21-activated Kinases journal April 2015
Made to measure – keeping Rho kinase at a distance journal April 2016
Small-angle scattering studies of biological macromolecules in solution journal September 2003
PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia journal November 1998
Automated matching of high- and low-resolution structural models journal February 2001
PRIMUS: a Windows PC-based system for small-angle scattering data analysis journal September 2003
ATSAS 2.1 – towards automated and web-supported small-angle scattering data analysis journal April 2007
DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering journal January 2009
Solving structures of protein complexes by molecular replacement with Phaser journal December 2006
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
REFMAC 5 for the refinement of macromolecular crystal structures journal March 2011
Presenting your structures: the CCP 4 mg molecular-graphics software journal March 2011
Using an in-vacuum CCD detector for simultaneous small- and wide-angle scattering at beamline X9 journal January 2013
PAK5, a New Brain-Specific Kinase, Promotes Neurite Outgrowth in N1E-115 Cells journal January 2002
p21-Activated Kinase 5 (Pak5) Localizes to Mitochondria and Inhibits Apoptosis by Phosphorylating BAD journal July 2003
AR and ER Interaction with a p21-Activated Kinase (PAK6) journal January 2002
AR and ER Interaction with a p21-Activated Kinase (PAK6) journal January 2002
PAK4 is activated via PI3K in HGF-stimulated epithelial cells journal October 2002
The Ras superfamily at a glance journal March 2005
PAK6 targets to cell–cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape journal November 2015
Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6 journal October 2013
Small-Angle X-Ray Scattering Reveals Compact Domain-Domain Interactions in the N-Terminal Region of Filamin C journal September 2014
Global Rigid Body Modeling of Macromolecular Complexes against Small-Angle Scattering Data journal August 2005
X-Ray Diffraction data from PAK4cat-PAK4N45-CDC42, source of 5UPK structure dataset January 2017
P21 activated kinases: Structure, regulation, and functions journal January 2014
Collaboration gets the most out of software journal September 2013

Cited By (10)

PAK4 signaling in health and disease: defining the PAK4–CREB axis journal February 2019
Additional file 1 of Study on the transcriptome for breast muscle of chickens and the function of key gene RAC2 on fibroblasts proliferation image January 2021
Additional file 2 of Study on the transcriptome for breast muscle of chickens and the function of key gene RAC2 on fibroblasts proliferation image January 2021
Additional file 9 of Study on the transcriptome for breast muscle of chickens and the function of key gene RAC2 on fibroblasts proliferation dataset January 2021
Synchrotron Big Data Science journal September 2018
Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis journal April 2019
Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region journal August 2018
The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences journal August 2019
A stemness screen reveals C3orf54/INKA1 as a promoter of human leukemia stem cell latency journal May 2019
Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region. text January 2018

Similar Records

3D structure analysis of PAKs: A clue to the rational design for affinity reagents and blockers
Journal Article · Sat Sep 15 20:00:00 EDT 2012 · Cellular Logistics (Online) · OSTI ID:1629289
Rac1-PAK2 pathway is essential for zebrafish heart regeneration
Journal Article · Fri Apr 15 00:00:00 EDT 2016 · Biochemical and Biophysical Research Communications · OSTI ID:22596331
PAK4 crystal structures suggest unusual kinase conformational movements
Journal Article · Wed Jan 31 19:00:00 EST 2018 · Biochimica et Biophysica Acta. Proteins and Proteomics · OSTI ID:1432881

Related Subjects

60 APPLIED LIFE SCIENCES
crystal structure
protein kinase
protein–protein interaction
signal transduction
small GTPase