Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6.
Gao, J., Ha, B.H., Lou, H.J., Morse, E.M., Zhang, R., Calderwood, D.A., Turk, B.E., Boggon, T.J.(2013) PLoS One 8: e77818-e77818
- PubMed: 24204982 
- 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.
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.