Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase.


Journal Article

Human VHR (vaccinia H1 related phosphatase) is a member of the dual-specificity phosphatases (DSPs) that often act on bisphosphorylated protein substrates. Unlike most DSPs, VHR displays a strong preference for dephosphorylating phosphotyrosine residues over phosphothreonine residues. Here we describe the 2.75 A crystal structure of the C124S inactive VHR mutant in complex with a bisphosphorylated peptide corresponding to the MAP kinase activation lip. This structure and subsequent biochemical studies revealed the basis for the strong preference for hydrolyzing phosphotyrosine within bisphosphorylated substrates containing -pTXpY-. In the structure, the two phospho residues are oriented into distinct pockets; the phosphotyrosine is bound in the exposed yet deep active site cleft while the phosphothreonine is loosely tethered into a nearby basic pocket containing Arg(158). As this structure is the first substrate-enzyme complex reported for the DSP family of enzymes, these results provide the first glimpse into how DSPs bind their protein substrates.

Full Text

Duke Authors

Cited Authors

  • Schumacher, MA; Todd, JL; Rice, AE; Tanner, KG; Denu, JM

Published Date

  • March 5, 2002

Published In

Volume / Issue

  • 41 / 9

Start / End Page

  • 3009 - 3017

PubMed ID

  • 11863439

Pubmed Central ID

  • 11863439

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi015799l


  • eng

Conference Location

  • United States