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Cracking the Phosphatase Code: Docking Interactions Determine Substrate Specificity

Many biological processes are regulated through alterations in the phosphorylation state of their protein components. Identifying the protein kinases and phosphatases that add and remove phosphate groups to these proteins is critical to understand cellular regulation. Most phosphoserine- and phosphothreonine-specific dephosphorylation is performed by a handful of protein phosphatases, each of which dephosphorylates sites that share little similarity in amino acid sequence. How do these enzymes recognize such diverse substrates with specificity? Studies show that several regions of the phosphatase that are not involved in catalysis are required for its recognition of protein partners. These regions, or docking surfaces, are conserved, and each binds weakly to a small, degenerate sequence motif (that is, a docking site) in a substrate or regulator of a phosphatase. Several of these weak interactions combine to achieve overall binding specificity. This Review, which contains 3 figures and 67 references, discusses genetic and structural studies that identify conserved docking surfaces in protein phosphatase type 1 (PP1) and the Ca2+-calmodulin–regulated phosphatase calcineurin, and show that some phosphatase inhibitors—for example, the immunosuppressants FK506 and cyclosporin A—act by interfering with substrate docking rather than with catalytic activity.

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Resource Type: Bibliography, Diagram, Illustration, Journal article/Issue, Review, Table
Audience Level: Undergraduate upper division 15-16, Graduate, Professional (degree program)

Author and Copyright

Authors and Editors: Jagoree Roy of Department of Biology, Stanford University, Martha S. Cyert of Department of Biology, Stanford University
Publisher: American Association for the Advancement of Science
Format: application/pdf, image/gif, image/jpeg, text/html
Copyright and other restrictions: Yes
Cost: Yes


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