1gfy
From Proteopedia
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RESIDUE 259 IS A KEY DETERMINANT OF SUBSTRATE SPECIFICITY OF PROTEIN-TYROSINE PHOSPHATASE 1B AND ALPHA
Contents |
Overview
The aim of this study was to define the structural elements that determine, the differences in substrate recognition capacity of two protein-tyrosine, phosphatases (PTPs), PTP1B and PTPalpha, both suggested to be negative, regulators of insulin signaling. Since the Ac-DADE(pY)L-NH(2) peptide is, well recognized by PTP1B, but less efficiently by PTPalpha, it was chosen, as a tool for these analyses. Calpha regiovariation analyses and primary, sequence alignments indicate that residues 47, 48, 258, and 259 (PTP1B, numbering) define a selectivity-determining region. By analyzing a set of, DADE(pY)L analogs with a series of PTP mutants in which these four, residues were exchanged between PTP1B and PTPalpha, either in combination, or alone, we here demonstrate that the key selectivity-determining residue, is 259. In PTPalpha, this residue is a glutamine causing steric hindrance, and in PTP1B a glycine allowing broad substrate recognition., Significantly, replacing Gln(259) with a glycine almost turns PTPalpha, into a PTP1B-like enzyme. By using a novel set of PTP inhibitors and x-ray, crystallography, we further provide evidence that Gln(259) in PTPalpha, plays a dual role leading to restricted substrate recognition (directly, via steric hindrance) and reduced catalytic activity (indirectly via, Gln(262)). Both effects may indicate that PTPalpha regulates highly, selective signal transduction processes.
Disease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this Structure
1GFY is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
Reference
Residue 259 is a key determinant of substrate specificity of protein-tyrosine phosphatases 1B and alpha., Peters GH, Iversen LF, Branner S, Andersen HS, Mortensen SB, Olsen OH, Moller KB, Moller NP, J Biol Chem. 2000 Jun 16;275(24):18201-9. PMID:10748206
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