4FIH

Catalytic domain of human PAK4 with QKFTGLPRQW peptide

Summary for 4FIH

• Entry DOI: 10.2210/pdb4fih/pdb
• Related: 4FIE 4FIF 4FIG 4FII 4FIJ
• Descriptor: Serine/threonine-protein kinase PAK 4 (2 entities in total)
• Functional Keywords: serine/threonine-protein kinase pak4, kinase domain, protein kinase, atp binding, phosphorylation, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O96013
• Total number of polymer chains: 1
• Total formula weight: 39123.13

Authors

Ha, B.H.,Boggon, T.J. (deposition date: 2012-06-08, release date: 2012-09-12, Last modification date: 2023-09-13)

Primary citation

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.
Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate.
Proc.Natl.Acad.Sci.USA, 109:16107-16112, 2012

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.

PubMed: 22988085
DOI: 10.1073/pnas.1214447109

Experimental method

X-RAY DIFFRACTION (1.97 Å)