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The PAK Ser/Thr kinases are important downstream effectors of the Rho family GTPases Cdc42 and Rac, partly mediating the role of these G proteins in cell proliferation and cytoskeletal rearrangements. As well as small G proteins, PAK interacts with the Cdc42/Rac exchange factor beta-PIX via the PIX SH3 domain and a nontypical Pro-rich region in PAK. This interaction is thought to affect the localization of PAK, as well as increased GTP/GDP exchange of Rac and Cdc42. We have determined the structure of the PIX-SH3/PAK peptide complex and shown that it differs from typical Src-like SH3/peptide complexes. The peptide makes contacts through the Pro-rich sequence in a similar way to standard SH3/peptide complexes, even though the Pro residue positions are not conserved. In addition, there are interactions with a Pro and Lys in the PAK, which are C-terminal to the conserved Arg found in all SH3-binding sequences. These contact a fourth binding pocket on the SH3 domain. We have measured the affinity of PIX-SH3 for the PAK peptide and found that it is of intermediate affinity. When PAK is activated, Ser-199 in the PIX-binding site is phosphorylated. This phosphorylation is sufficient to reduce the affinity for PIX 6-fold.

Structural analysis of the SH3 domain of beta-PIX and its interaction with alpha-p21 activated kinase (PAK)., Mott HR, Nietlispach D, Evetts KA, Owen D, Biochemistry. 2005 Aug 23;44(33):10977-83. PMID:16101281

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Evetts, K A. | Mott, H R. | Nietlispach, D. | Owen, D. | Sh3-peptide complex