Regulation of receptor protein-tyrosine phosphatase alpha by oxidative stress

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Abstract
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 H2O2, 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 H2O2 effect on RPTPα. H2O2 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, H2O2 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.