4FII

Catalytic domain of human PAK4 with RPKPLVDP peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate.

Ha, B.H.Davis, M.J.Chen, C.Lou, H.J.Gao, J.Zhang, R.Krauthammer, M.Halaban, R.Schlessinger, J.Turk, B.E.Boggon, T.J.

(2012) Proc Natl Acad Sci U S A 109: 16107-16112

  • DOI: https://doi.org/10.1073/pnas.1214447109
  • Primary Citation of Related Structures:  
    4FIE, 4FIF, 4FIG, 4FIH, 4FII, 4FIJ

  • PubMed Abstract: 

    The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not β-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.


  • Organizational Affiliation

    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PAK 4346Homo sapiensMutation(s): 0 
Gene Names: KIAA1142PAK4
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O96013 (Homo sapiens)
Explore O96013 
Go to UniProtKB:  O96013
PHAROS:  O96013
GTEx:  ENSG00000130669 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96013
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PAK 48Homo sapiensMutation(s): 0 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O96013 (Homo sapiens)
Explore O96013 
Go to UniProtKB:  O96013
PHAROS:  O96013
GTEx:  ENSG00000130669 
Entity Groups  
UniProt GroupO96013
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.557α = 90
b = 61.557β = 90
c = 181.771γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-12
    Type: Initial release
  • Version 1.1: 2012-09-26
    Changes: Database references
  • Version 1.2: 2012-10-31
    Changes: Database references
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description