spacer beta PIX-SH3 complexed with an atypical peptide from alpha-PAK
Primary citation
Title Structural Analysis of the SH3 Domain of beta-PIX and Its Interaction with alpha-p21 Activated Kinase (PAK)
Authors Mott,; Nietlispach,; Evetts,; Owen,
Journal BIOCHEMISTRYsearch vol:44, pag:10977-10983 (2005), Identifiers: PubMed ID (16101281)search DOI (10.1021/bi050374a)
Abstract 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.
MeSH terms Amino Acidssearch, Animalssearch, Cell Cycle Proteinssearch, Guanine Nucleotide Exchange Factorssearch, Guanosine Diphosphatesearch, Guanosine Triphosphatesearch, Humanssearch, Nuclear Magnetic Resonancesearch, Biomolecularsearch, Peptidessearch, Protein Bindingsearch, Protein Structuresearch, Quaternarysearch, Protein-Serine-Threonine Kinasessearch, Signal Transductionsearch, cdc42 GTP-Binding Proteinsearch, p21-Activated Kinasessearch, rac GTP-Binding Proteinssearch, src Homology Domainssearch