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Regulation of receptor protein-tyrosine phosphatase by oxidative stress
Christophe Blanchetot,
Leon G.J. Tertoolen, and
Jeroen den Hertog1
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, NL-3584 CT Utrecht, The Netherlands 1Corresponding author e-mail: hertog{at}niob.knaw.nl
Abstract:
The presence of two protein-tyrosine phosphatase (PTP) domainsis 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 intramolecularinteraction between the spacer region (Sp) and the C-terminusin RPTP prohibited intermolecular interactions. Interestingly,stress factors such as H2O2, UV and heat shock induced reversible,free radical-dependent, intermolecular interactions betweenRPTP and RPTP-SpD2, suggesting an inducible switch in conformationand binding. The catalytic site cysteine of RPTP-SpD2, Cys723,was required for the H2O2 effect on RPTP. H2O2 induced a rapid,reversible, Cys723-dependent conformational change in vivo,as detected by fluorescence resonance energy transfer, withcyan fluorescent protein (CFP) and yellow fluorescent protein(YFP) flanking RPTP-SpD2 in a single chimeric protein. Importantly,H2O2 treatment stabilized RPTP dimers, resulting in inactivation.We propose a model in which oxidative stress induces a conformationalchange in RPTP-D2, leading to stabilization of RPTP dimers,and thus to inhibition of RPTP activity.
by oxidative stress
prohibited intermolecular interactions. Interestingly, stress factors such as H2O2, UV and heat shock induced reversible, free radical-dependent, intermolecular interactions between RPTP
