Structural basis of protein phosphatase 1 regulation
Structural basis of protein phosphatase 1 regulation
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DOI：
10.1038/nature02582
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发表时间：
2004-06-17
期刊：
影响因子：
64.8
通讯作者：
Dominguez, R
中科院分区：
文献类型：
--
作者：
Terrak, M;Kerff, F;Dominguez, R
丝氨酸/苏氨酸（Ser/Thr）蛋白激酶和磷酸酶的协调和相互作用产生短暂磷酸化，这是许多生物过程的基本调节机制。人类基因组编码的丝氨酸/苏氨酸蛋白激酶远多于磷酸酶。尤其是蛋白磷酸酶1 (PP1)，它无处不在，并调节广泛的细胞功能，包括糖原代谢、细胞周期进程和肌肉松弛（1,2）。PP1已经进化出有效的催化机制，但缺乏底物特异性。底物特异性是通过与大量调控亚基的相互作用赋予PP1的。调控亚基通常是不相关的，但大多数具有RVxF基序，这是一个典型的pp1结合序列。在这里，我们在2.7埃分辨率下揭示了PP1和肌球蛋白磷酸酶靶向亚基MYPT1的34 kda n端结构域之间复合物的晶体结构。MYPT1是调节PP1在平滑肌松弛中的功能的蛋白(3)。MYPT1 RVxF基序的氨基端和羧基端结构元件的定位方式导致PP1催化裂口的明显重塑，有助于增加该复合物的肌球蛋白特异性。该结构对其他调控亚基对PP1活性的控制具有普遍意义。
The coordinated and reciprocal action of serine/threonine (Ser/Thr) protein kinases and phosphatases produces transient phosphorylation, a fundamental regulatory mechanism for many biological processes. The human genome encodes a far greater number of Ser/Thr protein kinases than of phosphatases. Protein phosphatase 1 (PP1), in particular, is ubiquitously distributed and regulates a broad range of cellular functions, including glycogen metabolism, cell-cycle progression and muscle relaxation(1,2). PP1 has evolved effective catalytic machinery but lacks substrate specificity. Substrate specificity is conferred upon PP1 through interactions with a large number of regulatory subunits. The regulatory subunits are generally unrelated, but most possess the RVxF motif, a canonical PP1-binding sequence. Here we reveal the crystal structure at 2.7 Angstrom resolution of the complex between PP1 and a 34-kDa N-terminal domain of the myosin phosphatase targeting subunit MYPT1. MYPT1 is the protein that regulates PP1 function in smooth muscle relaxation(3). Structural elements amino- and carboxy-terminal to the RVxF motif of MYPT1 are positioned in a way that leads to a pronounced reshaping of the catalytic cleft of PP1, contributing to the increased myosin specificity of this complex. The structure has general implications for the control of PP1 activity by other regulatory subunits.