Structural basis for regulation of protein phosphatase 1 by inhibitor-2

Thomas Hurley, Jie Yang, Lili Zhang, Kristie D. Goodwin, Qin Zou, Marc Cortese, A. Dunker, Anna De Paoli-Roach

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

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 2.5Å 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 α-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.

Original languageEnglish
Pages (from-to)28874-28883
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number39
DOIs
StatePublished - Sep 28 2007

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Protein Phosphatase 1
Phosphoprotein Phosphatases
Metal ions
Crystal structure
Amino Acids
Substrates
Metals
Ions
protein phosphatase inhibitor-1
protein phosphatase inhibitor-2
Inhibition (Psychology)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structural basis for regulation of protein phosphatase 1 by inhibitor-2. / Hurley, Thomas; Yang, Jie; Zhang, Lili; Goodwin, Kristie D.; Zou, Qin; Cortese, Marc; Dunker, A.; De Paoli-Roach, Anna.

In: Journal of Biological Chemistry, Vol. 282, No. 39, 28.09.2007, p. 28874-28883.

Research output: Contribution to journalArticle

Hurley, Thomas ; Yang, Jie ; Zhang, Lili ; Goodwin, Kristie D. ; Zou, Qin ; Cortese, Marc ; Dunker, A. ; De Paoli-Roach, Anna. / Structural basis for regulation of protein phosphatase 1 by inhibitor-2. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 39. pp. 28874-28883.
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