Cooperative mechanics of PR65 scaffold underlies the allosteric regulation of the phosphatase PP2A.
Cooperative mechanics of PR65 scaffold underlies the allosteric regulation of the phosphatase PP2A.
复制标题
PR65 支架的协同机制是磷酸酶 PP2A 变构调节的基础。
DOI：
10.1016/j.str.2023.02.012
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Bahar,Ivet
中科院分区：
文献类型：
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作者：
Kaynak,BurakT;Dahmani,ZakariaL;Doruker,Pemra;Banerjee,Anupam;Yang,Shang-Hua;Gordon,Reuven;Itzhaki,LauraS;Bahar,Ivet
PR 65是一种马蹄形支架，由15个HEAT（在亨廷顿蛋白、延伸因子3、蛋白磷酸酶2A和酵母激酶TOR 1中观察到）重复序列组成，与催化和调节亚基一起形成异源三聚体蛋白磷酸酶PP 2A。我们研究了PR 65在不同复杂程度的计算中使PP 2A酶活性的作用，包括结合联合收割机全原子和弹性网络模型的混合方法。我们的研究指出，这种支架的高度灵活性允许在紧凑和扩展构象之间的端到端距离波动为40-50 μ m。值得注意的是，PR 65的内在动力学促进与催化亚基的复合，并保留在PP 2A复合物中，使PR 65能够接合催化亚基的两个结构域，并在调节亚基的支持下为酶活性提供机械框架。特别是，在C-末端臂的重复内螺旋在变构介导PP 2A的集体动力学中起重要作用，指向调节PR 65功能的靶位点。
PR65, a horseshoe-shaped scaffold composed of 15 HEAT (observed in Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats, forms, together with catalytic and regulatory subunits, the heterotrimeric protein phosphatase PP2A. We examined the role of PR65 in enabling PP2A enzymatic activity with computations at various levels of complexity, including hybrid approaches that combine full-atomic and elastic network models. Our study points to the high flexibility of this scaffold allowing for end-to-end distance fluctuations of 40–50 Å between compact and extended conformations. Notably, the intrinsic dynamics of PR65 facilitates complexation with the catalytic subunit and is retained in the PP2A complex enabling PR65 to engage the two domains of the catalytic subunit and provide the mechanical framework for enzymatic activity, with support from the regulatory subunit. In particular, the intra-repeat coils at the C-terminal arm play an important role in allosterically mediating the collective dynamics of PP2A, pointing to target sites for modulating PR65 function.