Mechanisms of the scaffold subunit in facilitating protein phosphatase 2A methylation.
Mechanisms of the scaffold subunit in facilitating protein phosphatase 2A methylation.
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DOI：
10.1371/journal.pone.0086955
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Xing Y
中科院分区：
文献类型：
--
作者：
Stanevich V;Zheng A;Guo F;Jiang L;Wlodarchak N;Xing Y
生物必需蛋白磷酸酶2A(PP2A)的功能依赖于各种异三聚体全酶的形成，这涉及到PP2A支架(A)与催化(C或PP2Ac)亚基之间的稳定结合以及可变调节亚基的结合。全酶的组装受PP2Ac-Tail的羧甲基化的高度调控；PP2Ac的甲基化和A和C亚基的结合与PP2Ac的激活相耦合。在这里，我们发现PP2A特异性甲基转移酶LCMT-1对核心酶(A-C异源二聚体)的活性高于游离PP2Ac，A-亚基通过三种不同的机制促进PP2A甲基化：1)稳定适当的蛋白质折叠和PP2Ac的活性构象；2)限制PP2Ac-尾部的移动空间，以增强进入LCMT-1活性部位；以及3)LCMT-1与A-亚基N端热重复序列之间的弱静电相互作用。我们的结果揭示了A亚基在PP2A甲基化中的新功能和新机制，以及对PP2A活性、甲基化和全酶组装的一致控制。
The function of the biologically essential protein phosphatase 2A (PP2A) relies on formation of diverse heterotrimeric holoenzymes, which involves stable association between PP2A scaffold (A) and catalytic (C or PP2Ac) subunits and binding of variable regulatory subunits. Holoenzyme assembly is highly regulated by carboxyl methylation of PP2Ac-tail; methylation of PP2Ac and association of the A and C subunits are coupled to activation of PP2Ac. Here we showed that PP2A-specific methyltransferase, LCMT-1, exhibits a higher activity toward the core enzyme (A–C heterodimer) than free PP2Ac, and the A-subunit facilitates PP2A methylation via three distinct mechanisms: 1) stabilization of a proper protein fold and an active conformation of PP2Ac; 2) limiting the space of PP2Ac-tail movement for enhanced entry into the LCMT-1 active site; and 3) weak electrostatic interactions between LCMT-1 and the N-terminal HEAT repeats of the A-subunit. Our results revealed a new function and novel mechanisms of the A-subunit in PP2A methylation, and coherent control of PP2A activity, methylation, and holoenzyme assembly.
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