4KS7

Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6.

(2013) PLoS One 8: e77818-e77818

• PubMed: 24204982 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1371/journal.pone.0077818
• Primary Citation of Related Structures:  
  4KS7, 4KS8


• PubMed Abstract: 
  

  The p21-activated kinases (PAKs) are important effectors of Rho-family small GTPases. The PAK family consists of two groups, type I and type II, which have different modes of regulation and signaling. PAK6, a type II PAK, influences behavior and locomotor function in mice and has an ascribed role in androgen receptor signaling. Here we show that PAK6 has a peptide substrate specificity very similar to the other type II PAKs, PAK4 and PAK5 (PAK7). We find that PAK6 catalytic activity is inhibited by a peptide corresponding to its N-terminal pseudosubstrate. Introduction of a melanoma-associated mutation, P52L, into this peptide reduces pseudosubstrate autoinhibition of PAK6, and increases phosphorylation of its substrate PACSIN1 (Syndapin I) in cells. Finally we determine two co-crystal structures of PAK6 catalytic domain in complex with ATP-competitive inhibitors. We determined the 1.4 Å co-crystal structure of PAK6 with the type II PAK inhibitor PF-3758309, and the 1.95 Å co-crystal structure of PAK6 with sunitinib. These findings provide new insights into the structure-function relationships of PAK6 and may facilitate development of PAK6 targeted therapies.

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Organizational Affiliation: 

State Key Laboratory for Conservation and Utilization of Subtropical Agro-biosciences, The Key Laboratory of Ministry of Education for Microbial and Plant Genetic Engineering, and College of Life Science and Technology, Guangxi University, Nanning, Guangxi, China ; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.