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Regulation of receptor protein‐tyrosine phosphatase α by oxidative stress
Author(s) -
Blanchetot Christophe,
G.J.Tertoolen Leon,
den Hertog Jeroen
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.4.493
Subject(s) - biology , förster resonance energy transfer , protein tyrosine phosphatase , tyrosine , bimolecular fluorescence complementation , phosphatase , conformational change , biophysics , yellow fluorescent protein , biochemistry , transmembrane protein , oxidative phosphorylation , receptor , fluorescence , yeast , phosphorylation , physics , quantum mechanics , gene
The presence of two protein‐tyrosine phosphatase (PTP) domains is a striking feature in most transmembrane receptor PTPs (RPTPs). The function of the generally inactive membrane‐distal PTP domain (RPTP‐D2) is unknown. Here we report that an intramolecular interaction between the spacer region (Sp) and the C‐terminus in RPTPα prohibited intermolecular interactions. Interestingly, stress factors such as H 2 O 2 , UV and heat shock induced reversible, free radical‐dependent, intermolecular interactions between RPTPα and RPTPα‐SpD2, suggesting an inducible switch in conformation and binding. The catalytic site cysteine of RPTPα‐SpD2, Cys723, was required for the H 2 O 2 effect on RPTPα. H 2 O 2 induced a rapid, reversible, Cys723‐dependent conformational change in vivo , as detected by fluorescence resonance energy transfer, with cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) flanking RPTPα‐SpD2 in a single chimeric protein. Importantly, H 2 O 2 treatment stabilized RPTPα dimers, resulting in inactivation. We propose a model in which oxidative stress induces a conformational change in RPTPα‐D2, leading to stabilization of RPTPα dimers, and thus to inhibition of RPTPα activity.