Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme
Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme
复制标题
DOI：
10.1038/nature05351
复制
发表时间：
2007-01-04
期刊：
影响因子：
64.8
通讯作者：
Xu, Wenqing
中科院分区：
文献类型：
--
作者：
Cho, Uhn Soo;Xu, Wenqing
蛋白磷酸酶2A（PP 2A）是主要的Ser/Thr磷酸酶，其失调与多种人类癌症、阿尔茨海默病和对病原体感染的易感性增加相关。PP 2A在结构上是如何组织和功能上如何调节的尚不清楚。在这里，我们报告的晶体结构的AB 'C异源三聚体PP 2A全酶。该结构揭示了支架A亚基的HEAT重复形成马蹄形折叠，将催化C和调节B'亚基一起保持在同一侧。调节B'亚基形成假HEAT重复序列并与活性位点附近的C亚基相互作用，从而确定底物特异性。C亚基的甲基化羧基末端尾部与A和B'亚基之间界面处的高度负电荷区域相互作用，表明C亚基的C末端羧基甲基化通过中和电荷排斥促进B'亚基募集。总之，我们的结构结果为理解PP 2A组装、底物募集和调控奠定了重要基础。
Protein phosphatase 2A (PP2A) is a principal Ser/Thr phosphatase, the deregulation of which is associated with multiple human cancers, Alzheimer's disease and increased susceptibility to pathogen infections. How PP2A is structurally organized and functionally regulated remains unclear. Here we report the crystal structure of an AB'C heterotrimeric PP2A holoenzyme. The structure reveals that the HEAT repeats of the scaffold A subunit form a horseshoe-shaped fold, holding the catalytic C and regulatory B' subunits together on the same side. The regulatory B' subunit forms pseudo-HEAT repeats and interacts with the C subunit near the active site, thereby defining substrate specificity. The methylated carboxy-terminal tail of the C subunit interacts with a highly negatively charged region at the interface between A and B' subunits, suggesting that the C-terminal carboxyl methylation of the C subunit promotes B' subunit recruitment by neutralizing charge repulsion. Together, our structural results establish a crucial foundation for understanding PP2A assembly, substrate recruitment and regulation.