Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B

Salmeen, A., Andersen, J. N., Myers, M. P., Tonks, N. K., Barford, D. (December 2000) Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Molecular Cell, 6 (6). pp. 1401-1412. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/11163213
DOI: 10.1016/s1097-2765(00)00137-4

Abstract

The protein tyrosine phosphatase PTP1B is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase (IRK) activation segment. Here, by integrating crystallographic, kinetic, and PTP1B peptide binding studies, we define the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem pTyr residues at 1162 and 1163 such that pTyr-1162 is selected at the catalytic site and pTyr-1163 is located within an adjacent pTyr recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem pTyr-containing peptides relative to mono-pTyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity.

Item Type: Paper
Uncontrolled Keywords: SUBSTRATE-SPECIFICITY CRYSTAL-STRUCTURE PEPTIDE AUTOPHOSPHORYLATION KINASE SITE IDENTIFICATION SENSITIVITY OBESITY DOMAIN
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > insulin receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: Matt Covey
Date: December 2000
Date Deposited: 18 Dec 2013 19:50
Last Modified: 18 Dec 2013 19:50
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29022

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving