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首页> 外文期刊>Biochemistry >Structural analysis of the SH3 domain of beta-PIX and its interaction with alpha-p21 activated kinase (PAK)
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Structural analysis of the SH3 domain of beta-PIX and its interaction with alpha-p21 activated kinase (PAK)

机译：β-PIXSH3结构域的结构分析及其与α-p21活化激酶（PAK）的相互作用

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摘要

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 Rae 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.
机译：PAK Ser / Thr激酶是Rho家族GTPases Cdc42和Rac的重要下游效应子，部分介导了这些G蛋白在细胞增殖和细胞骨架重排中的作用。除小G蛋白外，PAK还通过PIX SH3域和PAK中非典型的Pro-rich区域与Cdc42 / Rac交换因子β-Pix相互作用。这种相互作用被认为会影响PAK的本地化，以及Rae和Cdc42的GTP / GDP交换增加。我们已经确定了PIX-SH3 / PAK肽复合物的结构，并表明它与典型的Src样SH3 /肽复合物不同。即使Pro残基的位置不保守，该肽也可以通过富含Pro的序列与标准SH3 /肽复合物进行接触。另外，在PAK中存在与Pro和Lys的相互作用，其在所有SH3结合序列中都存在于保守的Arg的C末端。这些接触SH3结构域上的第四个结合口袋。我们测量了PIX-SH3对PAK肽的亲和力，发现它具有中等亲和力。激活PAK后，PIX结合位点中的Ser-199被磷酸化。这种磷酸化足以降低对PIX的亲和力6倍。

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