Structural basis for regulation of protein phosphatase 1 by inhibitor-2
Structural basis for regulation of protein phosphatase 1 by inhibitor-2
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DOI：
10.1074/jbc.m703472200
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发表时间：
2007-09-28
影响因子：
4.8
通讯作者：
DePaoli-Roach, Anna A.
中科院分区：
文献类型：
--
作者：
Hurley, Thomas D.;Yang, Jie;DePaoli-Roach, Anna A.
1型蛋白磷酸酶(PP1)的功能特异性取决于相关的调节/靶向和抑制亚基。为了深入了解抑制物-2对PP1的调节机制，我们将该复合体的晶体结构解析为2.5埃分辨率。我们的研究表明，当与PP1c络合时，I-2获得了三个有序区：第1位，残基12-17，与许多PP1调节剂识别的区域相邻；第2位，氨基酸44-56，通过一个意外的序列KSQKW沿RVXF结合槽相互作用；第3位，130-169残基，形成跨越底物结合裂隙的α螺旋区域。具体地说，残基148-151在催化中心相互作用，取代必要的金属离子，这是PP1c快速抑制和较慢失活的原因。因此，我们的结构为PP1抑制和随后重新激活的机制提供了新的见解，对PP1的生理调节具有广泛的意义，并突出了磷酸蛋白磷酸酶家族成员之间共同的抑制相互作用。
The functional specificity of type 1 protein phosphatases (PP1) depends on the associated regulatory/targeting and inhibitory subunits. To gain insights into the mechanism of PP1 regulation by inhibitor-2, an ancient and intrinsically disordered regulator, we solved the crystal structure of the complex to 2.5 angstrom resolution. Our studies show that, when complexed with PP1c, I-2 acquires three regions of order: site 1, residues 12-17, binds adjacent to a region recognized by many PP1 regulators; site 2, amino acids 44-56, interacts along the RVXF binding groove through an unsuspected sequence, KSQKW; and site 3, residues 130-169, forms alpha-helical regions that lie across the substrate-binding cleft. Specifically, residues 148-151 interact at the catalytic center, displacing essential metal ions, accounting for both rapid inhibition and slower inactivation of PP1c. Thus, our structure provides novel insights into the mechanism of PP1 inhibition and subsequent reactivation, has broad implications for the physiological regulation of PP1, and highlights common inhibitory interactions among phosphoprotein phosphatase family members.