Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate
Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate
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DOI：
10.1073/pnas.1214447109
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发表时间：
2012-10-02
影响因子：
11.1
通讯作者：
Boggon, Titus J.
中科院分区：
文献类型：
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作者：
Ha, Byung Hak;Davis, Matthew J.;Boggon, Titus J.
II型p21激活激酶（PAK）是参与细胞运动、存活和增殖的RH 0家族GTP酶的关键效应物。使用结构指导的方法，我们发现，II型PAKs的调节由一个N-末端的自抑制性pseudosubstrate基序集中在一个关键的脯氨酸残基，这种调节独立于激活环磷酸化。我们确定了全长PAK 4或其催化结构域的六种X射线晶体结构，这证明了假底物结合到具有磷酸化活化环的活性状态的分子基础。我们发现，全长PAK 4是组成性自抑制，但突变的假底物释放这种抑制，并导致增加的磷酸化的凋亡调节蛋白Bcl-2/Bcl-X-L拮抗剂引起细胞死亡和细胞形态学变化。我们还发现，PAK 6是由假底物区域，表明一个共同的II型PAK自动调节机制。最后，我们发现Src SH 3可以激活PAK 4，而β-PIX SH 3不能。我们对II类PAK监管有独特的理解。
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.