Crystallographic analysis of protein phosphatase 2A

描述（由申请人提供）：可逆蛋白质Ser/Thr磷酸化是细胞调节的基本机制。虽然在人类基因组中已经鉴定了超过400种Ser/Thr激酶，但是只有少数催化亚基用于Ser/Thr磷酸酶。与之前磷酸酶具有组成性活性的假设相反，最近的工作表明，许多磷酸酶受到高度调节，主要是通过与不同的调节或靶向亚基形成蛋白质复合物来实现的。该提案的重点是蛋白磷酸酶2A（PP 2A），这是一种调节细胞活性几乎所有方面的中心人类磷酸酶，是一种重要的肿瘤抑制因子。PP 2A的失调与乳腺癌、肺癌和结肠直肠癌以及阿尔茨海默病和对病毒和寄生虫感染的易感性有关。典型的PP 2A全酶含有支架A亚基、催化C亚基和许多调节B亚基中的一种，所述调节B、B'和B”家族。尽管功能的重要性，它仍然是在很大程度上是未知的PP 2A如何形成一个功能复合物和复杂的组装是如何调节。在这个建议中，我们的目标是提供结构的基础上了解PP 2A异源三聚体复合物的组装和调节，通过X射线晶体学和相关的生化分析的结构测定。我们的研究不仅对于理解蛋白质Ser/Thr去磷酸化的调节，而且对于设计PP 2A激活剂，无论是稳定功能PP 2A组装或破坏PP 2A抑制蛋白相互作用都很重要。此类化合物可用于癌症治疗。

DESCRIPTION (provided by applicant): Reversible protein Ser/Thr phosphorylation is a fundamental mechanism for cell regulation. While more than 400 Ser/Thr kinases have been identified in the human genome, there are only a few catalytic subunits for Ser/Thr phosphatases. In contrast to the previous assumption that phosphatases are constitutively active, recent work has shown that many phosphatases are highly regulated, largely through the formation of protein complexes with different regulatory or targeting subunits. This proposal focuses on the protein phosphatase 2A (PP2A), a central human phosphatase that regulates almost all aspects of cellular activity and is a critical tumor suppressor. Deregulation of PP2A is associated with breast, lung, and colorectal cancers as well as Alzheimer's Disease and susceptibility to viral and parasitic infection. A typical PP2A holoenzyme contains a scaffold A subunit, a catalytic C subunit and one of many regulatory B subunits, which are divided into B, B' and B" families. Despite the functional importance, it is still largely unknown how PP2A forms a functional complex and how the complex assembly is regulated. In this proposal, we aim to provide the structural basis for understanding the assembly and regulation of PP2A heterotrimeric complexes, through structural determination by X-ray crystallography and related biochemical analysis. Our study will be important not only for understanding the regulation of protein Ser/Thr dephosphorylation, but also for designing PP2A activators that either stabilize functional PP2A assembly or disrupt PP2A-inhibitory protein interactions. Such compounds can be useful for cancer treatment.