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295 a.a.
59 a.a.
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Key reference
DOI no: 10.1074/jbc.M703472200 J Biol Chem 282:28874-28883 (2007) PubMed id: 17636256
Structural basis for regulation of protein phosphatase 1 by inhibitor-2. T.D.Hurley, J.Yang, L.Zhang, K.D.Goodwin, Q.Zou, M.Cortese, A.K.Dunker, A.A.Depaoli-Roach. 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 2.5A 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.
Selected figure(s)
Figure 2.
FIGURE 2. Observed structure of the PP1c·I-2 complex. a, the ribbon structure of PP1c
[A]-weighted electron density contoured at one standard deviation for residues 12-17 of I-2 (b), residues 44-56 of I-2 (c), and residues 145-155 of I-2 (d). Figs. 2, 4(b-d), and 5, 6 and 7 were produced using SPDB-Viewer (54) and POV-Ray for Windows (55).
Figure 6.
FIGURE 6. Common and unique interactions across the surface of PP1c. a, structure alignment of residues from R[GL] (green), MYPT1 (blue), and I-2 (red) that bind along the RVXF binding groove. The identity of the residues at each position is indicated using the single-amino acid code in the appropriate color. b, structure alignment of the PP1c·MYPT1 (Protein Data Bank code 1wao, blue and red, respectively) complex to the PP1c
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 28874-28883) copyright 2007. Figures were selected by the author.
Literature references that cite this PDB file's key reference
PubMed id Reference
19887526 Y.C.Huang, Y.C.Chen, H.J.Tsay, C.L.Chyan, C.Y.Chen, H.B.Huang, and T.H.Lin (2010).
The effect of PKA-phosphorylation on the structure of inhibitor-1 studied by NMR spectroscopy.J Biochem, 147, 273-278.
19412530 B.Mészáros, I.Simon, and Z.Dosztányi (2009).
Prediction of protein binding regions in disordered proteins.PLoS Comput Biol, 5, e1000376.
19332797 S.Martínez-Martínez, L.Genescà, A.Rodríguez, A.Raya, E.Salichs, F.Were, M.D.López-Maderuelo, J.M.Redondo, and S.de la Luna (2009).
The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators.Proc Natl Acad Sci U S A, 106, 6117-6122.
19273587 S.Mehta, H.Li, P.G.Hogan, and K.W.Cunningham (2009).
Domain architecture of the regulators of calcineurin (RCANs) and identification of a divergent RCAN in yeast.Mol Cell Biol, 29, 2777-2793.
18394161 B.Suchanova, and R.Tuma (2008).
Folding and assembly of large macromolecular complexes monitored by hydrogen-deuterium exchange and mass spectrometry.Microb Cell Fact, 7, 12.
19000314 G.B.Moorhead, L.Trinkle-Mulcahy, M.Nimick, V.De Wever, D.G.Campbell, R.Gourlay, Y.W.Lam, and A.I.Lamond (2008).
Displacement affinity chromatography of protein phosphatase one (PP1) complexes.BMC Biochem, 9, 28.
19020623 R.A.Hanna, R.L.Campbell, and P.L.Davies (2008).
Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin.Nature, 456, 409-412.
PDB code: 3bow The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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