The receptor PTPRU is a redox sensitive pseudophosphatase

The dynamic regulation of protein tyrosine phosphorylation is a critical feature of intercellular communication and is regulated by the actions of kinases and phosphatases. The receptor-linked protein tyrosine phosphatases (RPTPs) are key signaling molecules that possess an extracellular domain and intracellular phosphatase domains. Most human RPTPs have tandem intracellular tyrosine phosphatase domains: a catalytically active membrane proximal (D1) domain; and a membrane distal (D2) inactive pseudophosphatase domain. The receptor PTPRU plays a role in development, multiple cancers and has been implicated in the dephosphorylation of cell adhesion proteins. However, PTPRU has a non-canonical D1 domain containing several sequence variations in key catalytic loops that suggest it may function using a mechanism distinct from related RPTPs. Here, we demonstrate through biochemical and structural studies that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. We show that PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and determine that this is due to substantial disorder in the substrate-binding pocket as well as rearrangement of the catalytic loop such that the active site cysteine is occluded. We also show that this cysteine can form an intramolecular disulfide bond with a vicinal backdoor cysteine. Further, we demonstrate that the PTPRU D2 domain can recruit substrates of related RPTPs suggesting that this pseudophosphatase functions by competing with active phosphatases for the binding of substrates involved in cell adhesion. Therefore, PTPRU is a bona-fide pseudophosphatase and its functional role in cell signaling is via a non-catalytic mechanism.