The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1

T-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells. TCPTP is a critical component of a variety of key signaling pathways that are directly associated with the formation of cancer and inflammation. Thus, understanding the molecular mechanism of TCPTP activation and regulation is essential for the development of TCPTP therapeutics. Under basal conditions, TCPTP is largely inactive, although how this is achieved is poorly understood. Thus, in this study we used Intra and inter molecular CX-MS analysis to reveal molecular mechanism of TCPTP activity regulation, our both intra- and inter- molecular CX-MS analysis result shows that the C-terminal intrinsically disordered tail of TCPTP directly bind on the surface of catalytic domain and function as autoinhibitory element to control the TCPTP catalytic activity.

T细胞蛋白酪氨酸磷酸酶（T-Cell Protein Tyrosine Phosphatase，TCPTP，PTPN2）是一类在人体细胞中普遍表达的非受体型蛋白酪氨酸磷酸酶。TCPTP是多种与癌症及炎症发生直接相关的核心信号通路的关键组成成分。因此，阐明TCPTP激活与调控的分子机制，对于TCPTP靶向治疗药物的开发具有至关重要的意义。在基础静息状态下，TCPTP整体处于失活状态，但其具体调控机制目前仍不甚明晰。为此，本研究采用分子内与分子间CX-MS分析手段，揭示了TCPTP活性调控的分子机制：我们的分子内及分子间CX-MS分析结果表明，TCPTP的C端固有无序尾段可直接结合于其催化结构域表面，并作为自抑制元件调控TCPTP的催化活性。