The structure of p85ni in class IA phosphoinositide 3-kinase exhibits interdomain disorder.
The structure of p85ni in class IA phosphoinositide 3-kinase exhibits interdomain disorder.
复制标题
IA类磷酸肌醇3-激酶中p85ni的结构表现出域间紊乱。
DOI：
10.1021/bi902171d
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发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Gerfen,GaryJ
中科院分区：
文献类型：
--
作者：
Sen,KIlker;Wu,Haiyan;Backer,JonathanM;Gerfen,GaryJ
IA类PI 3-激酶的调节涉及调节亚基（p85）对催化亚基（p110）的抑制和稳定。调节是通过两个主要的接触：一个稳定的界面，涉及衔接子结合结构域（ABD）的p110和间SH 2（iSH 2）结构域的p85和调节之间的相互作用的N-末端SH 2（nSH 2）结构域的p85和螺旋结构域的p110。在本研究中，我们研究了p85α的nSH 2和iSH 2的相对取向，使用定点自旋标记和脉冲EPR。令人惊讶的是，距离测量和距离分布表明，nSH 2结构域是高度无序的相对于iSH 2结构域。基于EPR距离限制的分子建模表明，nSH 2结构域以铰链样方式移动，在iSH 2结构域的近端周围采样环面空间。这些数据具有重要意义的机制，其中p85/p110二聚体的磷酸肽调节。
Regulation of the class IA PI 3-kinase involves inhibition and stabilization of the catalytic subunit (p110) by the regulatory subunit (p85). Regulation is achieved by two major contacts: a stable interface involving the adapter-binding domain (ABD) of p110 and the inter-SH2 (iSH2) domain of p85 and a regulatory interaction between the N-terminal SH2 (nSH2) domain of p85 and the helical domain of p110. In the present study, we have examined the relative orientation of the nSH2 and iSH2 of p85α using site-directed spin labeling and pulsed EPR. Surprisingly, both distance measurements and distance distributions suggest that the nSH2 domain is highly disordered relative to the iSH2 domain. Molecular modeling based on EPR distance restraints suggests that the nSH2 domain moves in a hinge-like manner, sampling a torus space around the proximal end of the iSH2 domain. These data have important implications for the mechanism by which p85/p110 dimers are regulated by phosphopeptides.