4.8 Article

Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1214447109

关键词

autoregulation; protein kinase; RHO GTPase effector; signaling

资金

  1. National Institutes of Health [GM102262, GM079498]
  2. China Scholarship Council [2011666003]
  3. Guangxi University
  4. Yale SPORE in Skin Cancer Grant [CA121974]
  5. Gilead Sciences Grant [YG-001-11]

向作者/读者索取更多资源

The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X-L antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not beta-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据