The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising 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 that 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 binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.

受体连接蛋白酪氨酸磷酸酶 (RPTP) 通过控制细胞磷酸酪氨酸水平，是细胞间通讯的关键调节因子。大多数人类 RPTP 具有细胞外受体结构域和串联细胞内磷酸酶结构域：包括活性近端膜 (D1) 结构域和无活性远端 (D2) 假磷酸酶结构域。在这里，我们证明 PTPRU 在 RPTP 中是独一无二的，因为它拥有两个假磷酸酶结构域。 PTPRU-D1 对一系列磷酸化底物没有表现出可检测到的催化活性，我们表明这是由于多种结构重排导致活性位点袋不稳定并阻断催化半胱氨酸。氧化后，该半胱氨酸与邻近的“后门”半胱氨酸形成分子内二硫键，这一过程被认为可逆地灭活相关磷酸酶。重要的是，尽管不存在催化活性，PTPRU 仍能结合相关磷酸酶的底物，强烈表明这种假磷酸酶通过与活性磷酸酶竞争底物的结合而在酪氨酸磷酸化中起作用。