The receptor PTPRU is a redox sensitive pseudophosphatase

ain M. Hay, Gareth W. Fearnley, Pablo Rios, Maja Köhn, Hayley J. Sharpe, Janet E. Deane

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Received Date: 15th November 19

The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phopshotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: an active membrane proximal (D1) domain; and an inactive distal (D2) “pseudophosphatase” domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU retains the capacity to bind substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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