Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor

被引：41

作者：

Eto, Masumi ^{[1
]}

Kitazawa, Toshio ^{[2
]}

Matsuzawa, Fumiko ^{[3
]}

Aikawa, Sei-Ichi ^{[3
]}

Kirkbride, Jason A. ^{[1
]}

Isozumi, Noriyoshi ^{[4
]}

Nishimura, Yumi ^{[4
]}

Brautigan, David L. ^{[5
]}

Ohki, Shin-Ya ^{[4
]}

机构：

[1] Thomas Jefferson Univ, Dept Mol Physiol & Biophys, Philadelphia, PA 19107 USA

[2] Boston Biomed Res Inst, Watertown, MA 02472 USA

[3] Tokyo Metropolitan Inst Med Sci, Dept Clin Genet, Bunkyo Ku, Tokyo 1138613, Japan

[4] JAIST, CNMT, Tatsunokuchi, Ishikawa 9231292, Japan

[5] Univ Virginia, Sch Med, Ctr Cell Signaling, Charlottesville, VA 22908 USA

来源：

STRUCTURE | 2007年 / 15卷 / 12期

关键词：

D O I：

10.1016/j.str.2007.10.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Phosphorylation of endogenous inhibitor proteins for type-1 Ser/Thr phosphatase (PP1) provides a mechanism for reciprocal coordination of kinase and phosphatase activities. A myosin phosphatase inhibitor protein CPI-17 is phosphorylated at Thr38 through G-protein-mediated signals, resulting in a >1000-fold increase in inhibitory potency. We show here the solution NMR structure of phospho-T38-CPI-17 with rmsd of 0.36 +/- 0.06 angstrom for the backbone secondary structure, which reveals how phosphorylation triggers a conformational change and exposes an inhibitory surface. This active conformation is stabilized by the formation of a hydrophobic core of intercalated side chains, which is not formed in a phospho-mimetic D38 form of CPl-17. Thus, the profound increase in potency of CPI-17 arises from phosphorylation, conformational change, and hydrophobic stabilization of a rigid structure that poses the phosphorylated residue on the protein surface and restricts its hydrolysis by myosin phosphatase. Our results provide structural insights into transduction of kinase signals by PP1 inhibitor proteins.

引用

页码：1591 / 1602

页数：12