Regulation of receptor protein-tyrosine phosphatase α by oxidative stress

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) a...

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Bibliographic Details
Published in:The EMBO journal 2002-02, Vol.21 (4), p.493-503
Main Authors: Blanchetot, Christophe, G.J.Tertoolen, Leon, den Hertog, Jeroen
Format: Article
Language:English
Subjects:
Catalytic Domain
Cell Line
Dimerization
EMBO37
Energy Transfer
Fluorescence
FRET
Hot Temperature
Humans
Hydrogen Peroxide - pharmacology
Luminescent Proteins - genetics
Oxidative Stress
Protein Conformation
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - chemistry
Protein Tyrosine Phosphatases - metabolism
protein-tyrosine-phosphatase receptors
Receptors, Cell Surface - antagonists & inhibitors
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - metabolism
regulation
RPTP
Ultraviolet Rays
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Summary: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.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/21.4.493