Methylation-regulated decommissioning of multimeric PP2A complexes.
Methylation-regulated decommissioning of multimeric PP2A complexes.
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DOI：
10.1038/s41467-017-02405-3
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发表时间：
2017-12-22
影响因子：
16.6
通讯作者：
Xing Y
中科院分区：
文献类型：
--
作者：
Wu CG;Zheng A;Jiang L;Rowse M;Stanevich V;Chen H;Li Y;Satyshur KA;Johnson B;Gu TJ;Liu Z;Xing Y
信号复合物的动态组装/拆卸对细胞功能至关重要。专门的潜伏和激活分子伴侣控制蛋白磷酸酶2A（PP 2A）全酶的生物合成，包含一个共同的支架和催化亚基和一个可变的调节亚基。在这里，我们表明，蝴蝶形的TIPRL（TOR信号通路调节器），使高度整合的多分支与PP 2A催化亚基的接触，选择性的未甲基化的尾巴和扰动/失活的磷酸酶活性位点。TIPRL还与支架亚基进行不寻常的摆动接触，允许TIPRL而不是重叠的调节亚基耐受疾病相关的PP 2A突变，导致全酶组装减少和突变PP 2A的失活增强。引人注目的是，TIPRL和潜伏伴侣α4协调将活性全酶分解成潜伏的PP 2A，严格受甲基化控制。我们的研究揭示了甲基化反应性失活和全酶分解的机制，说明了调控/信号传导、动态复杂分解以及癌症和智力残疾中的疾病突变的复杂性。蛋白磷酸酶2A（PP 2A）形成不同的全酶，但对这些重要的信号复合物的分解知之甚少。在这里，作者提出的晶体结构的PP 2A绑定到TOR信号通路调节器（TIPRL），并提供见解甲基化依赖的拆卸PP 2A holenzymes。
Dynamic assembly/disassembly of signaling complexes are crucial for cellular functions. Specialized latency and activation chaperones control the biogenesis of protein phosphatase 2A (PP2A) holoenzymes that contain a common scaffold and catalytic subunits and a variable regulatory subunit. Here we show that the butterfly-shaped TIPRL (TOR signaling pathway regulator) makes highly integrative multibranching contacts with the PP2A catalytic subunit, selective for the unmethylated tail and perturbing/inactivating the phosphatase active site. TIPRL also makes unusual wobble contacts with the scaffold subunit, allowing TIPRL, but not the overlapping regulatory subunits, to tolerate disease-associated PP2A mutations, resulting in reduced holoenzyme assembly and enhanced inactivation of mutant PP2A. Strikingly, TIPRL and the latency chaperone, α4, coordinate to disassemble active holoenzymes into latent PP2A, strictly controlled by methylation. Our study reveals a mechanism for methylation-responsive inactivation and holoenzyme disassembly, illustrating the complexity of regulation/signaling, dynamic complex disassembly, and disease mutations in cancer and intellectual disability. Protein phosphatase 2A (PP2A) forms different holoenzymes but little is known about the disassembly of these important signalling complexes. Here the authors present the crystal structure of PP2A bound to TOR signaling pathway regulator (TIPRL) and give insights into the methylation-dependent disassembly of PP2A holenzymes.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8.8
作者：
Guo F;Wan L;Zheng A;Stanevich V;Wei Y;Satyshur KA;Shen M;Lee W;Kang Y;Xing Y
通讯作者：
Xing Y
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16.8
作者：
Chen, Yu;Xu, Yanhui;Shi, Yigong
通讯作者：
Shi, Yigong
影响因子：
4.8
作者：
Lee, Jocelyn A.;Pallas, David C.
通讯作者：
Pallas, David C.