Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 8 December 2009
Vol. 2, Issue 100, p. re9
[DOI: 10.1126/scisignal.2100re9]


Cracking the Phosphatase Code: Docking Interactions Determine Substrate Specificity

Jagoree Roy and Martha S. Cyert*

Department of Biology, Stanford University, 371 Serra Mall, Stanford, CA 94305–5020, USA.

Abstract: Phosphoserine- and phosphothreonine-directed phosphatases display remarkable substrate specificity, yet the sites that they dephosphorylate show little similarity in amino acid sequence. Studies reveal that docking interactions are key for the recognition of substrates and regulators by two conserved phosphatases, protein phosphatase 1 (PP1) and the Ca2+-calmodulin–dependent phosphatase calcineurin. In each case, a small degenerate sequence motif in the interacting protein directs low-affinity binding to a docking surface on the phosphatase that is distinct from the active site; several such interactions combine to confer overall binding specificity. Some docking surfaces are conserved, such as a hydrophobic groove on a face opposite the active site that serves as a major recognition surface for the "RVxF" motif of proteins that interact with PP1 and the "PxIxIT" motif of substrates of calcineurin. Secondary motifs combine with this primary targeting sequence to specify phosphatase binding. A comprehensive interactome for mammalian PP1 was described, analysis of which defines several PP1-binding motifs. Studies of "LxVP," a secondary calcineurin-binding sequence, establish that this motif is a conserved feature of calcineurin substrates and that the immunosuppressants FK506 and cyclosporin A inhibit the phosphatase by interfering with LxVP-mediated docking.

* Corresponding author. E-mail, mcyert{at}

Citation: J. Roy, M. S. Cyert, Cracking the Phosphatase Code: Docking Interactions Determine Substrate Specificity. Sci. Signal. 2, re9 (2009).

Read the Full Text

Evolution of Bacterial-Like Phosphoprotein Phosphatases in Photosynthetic Eukaryotes Features Ancestral Mitochondrial or Archaeal Origin and Possible Lateral Gene Transfer.
R. G. Uhrig, D. Kerk, and G. B. Moorhead (2013)
Plant Physiology 163, 1829-1843
   Abstract »    Full Text »    PDF »
A Calcineurin-dependent Switch Controls the Trafficking Function of {alpha}-Arrestin Aly1/Art6.
A. F. O'Donnell, L. Huang, J. Thorner, and M. S. Cyert (2013)
J. Biol. Chem. 288, 24063-24080
   Abstract »    Full Text »    PDF »
Genetic Bypass of Aspergillus nidulans crzA Function in Calcium Homeostasis.
R. S. Almeida, O. Loss, A. C. Colabardini, N. A. Brown, E. Bignell, M. Savoldi, S. Pantano, M. H. S. Goldman, H. N. Arst Jr, and G. H. Goldman (2013)
g3 3, 1129-1141
   Abstract »    Full Text »    PDF »
Engineering A-kinase Anchoring Protein (AKAP)-selective Regulatory Subunits of Protein Kinase A (PKA) through Structure-based Phage Selection.
M. G. Gold, D. M. Fowler, C. K. Means, C. T. Pawson, J. J. Stephany, L. K. Langeberg, S. Fields, and J. D. Scott (2013)
J. Biol. Chem. 288, 17111-17121
   Abstract »    Full Text »    PDF »
A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury.
A. M. Slupe, R. A. Merrill, K. H. Flippo, M. A. Lobas, J. C. D. Houtman, and S. Strack (2013)
J. Biol. Chem. 288, 12353-12365
   Abstract »    Full Text »    PDF »
A. A. Danielsen, M. D. Parker, S. Lee, W. F. Boron, C. Aalkjaer, and E. Boedtkjer (2013)
J. Biol. Chem. 288, 8146-8155
   Abstract »    Full Text »    PDF »
A High-throughput Assay for Phosphoprotein-specific Phosphatase Activity in Cellular Extracts.
A. K. Bose and K. A. Janes (2013)
Mol. Cell. Proteomics 12, 797-806
   Abstract »    Full Text »    PDF »
G-actin regulates the shuttling and PP1 binding of the RPEL protein Phactr1 to control actomyosin assembly.
M. Wiezlak, J. Diring, J. Abella, S. Mouilleron, M. Way, N. Q. McDonald, and R. Treisman (2012)
J. Cell Sci. 125, 5860-5872
   Abstract »    Full Text »    PDF »
Calcineurin regulates endothelial barrier function by interaction with and dephosphorylation of myosin phosphatase.
B. Kolozsvari, E. Bako, B. Becsi, A. Kiss, A. Czikora, A. Toth, G. Vamosi, P. Gergely, and F. Erdodi (2012)
Cardiovasc Res 96, 494-503
   Abstract »    Full Text »    PDF »
The WNK/SPAK and IRBIT/PP1 Pathways in Epithelial Fluid and Electrolyte Transport.
S. Park, J. H. Hong, E. Ohana, and S. Muallem (2012)
Physiology 27, 291-299
   Abstract »    Full Text »    PDF »
Cell Surface Expression of the Major Amyloid-{beta} Peptide (A{beta})-degrading Enzyme, Neprilysin, Depends on Phosphorylation by Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK) and Dephosphorylation by Protein Phosphatase 1a.
N. Kakiya, T. Saito, P. Nilsson, Y. Matsuba, S. Tsubuki, N. Takei, H. Nawa, and T. C. Saido (2012)
J. Biol. Chem. 287, 29362-29372
   Abstract »    Full Text »    PDF »
Differential regulation of a CLC anion channel by SPAK kinase ortholog-mediated multisite phosphorylation.
H. Miyazaki and K. Strange (2012)
Am J Physiol Cell Physiol 302, C1702-C1712
   Abstract »    Full Text »    PDF »
The C2 Domain Protein Cts1 Functions in the Calcineurin Signaling Circuit during High-Temperature Stress Responses in Cryptococcus neoformans.
E. F. Aboobakar, X. Wang, J. Heitman, and L. Kozubowski (2011)
Eukaryot. Cell 10, 1714-1723
   Abstract »    Full Text »    PDF »
Overview: The Maturing of Proteomics in Cardiovascular Research.
J. E. Van Eyk (2011)
Circ. Res. 108, 490-498
   Abstract »    Full Text »    PDF »
Multiple Pathways for Protein Phosphatase 1 (PP1) Regulation of Na-K-2Cl Cotransporter (NKCC1) Function: THE N-TERMINAL TAIL OF THE Na-K-2Cl COTRANSPORTER SERVES AS A REGULATORY SCAFFOLD FOR Ste20-RELATED PROLINE/ALANINE-RICH KINASE (SPAK) AND PP1.
K. B. Gagnon and E. Delpire (2010)
J. Biol. Chem. 285, 14115-14121
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882