| First Author | Wen Y | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 15 | Pages | 4923-4936 |
| PubMed ID | 32139509 | Mgi Jnum | J:286826 |
| Mgi Id | MGI:6404687 | Doi | 10.1074/jbc.RA119.011808 |
| Citation | Wen Y, et al. (2020) RPTPalpha phosphatase activity is allosterically regulated by the membrane-distal catalytic domain. J Biol Chem 295(15):4923-4936 |
| abstractText | Receptor-type protein tyrosine phosphatase alpha (RPTPalpha) is an important positive regulator of SRC kinase activation and a known promoter of cancer growth, fibrosis, and arthritis. The domain structure of RPTPs comprises an extracellular region, a transmembrane helix, and two tandem intracellular catalytic domains referred to as D1 and D2. The D2 domain of RPTPs is believed to mostly play a regulatory function; however, no regulatory model has been established for RPTPalpha-D2 or other RPTP-D2 domains. Here, we solved the 1.8 A resolution crystal structure of the cytoplasmic region of RPTPalpha, encompassing D1 and D2, trapped in a conformation that revealed a possible mechanism through which D2 can allosterically inhibit D1 activity. Using a D2-truncation RPTPalpha variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTPalpha phosphatase activity and identified a (405)PFTP(408) motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTPalpha variant in HEK293T cells enhanced SRC activation, supporting the relevance of our proposed D2-mediated regulation mechanism in cell signaling. There is emerging interest in the development of allosteric inhibitors of RPTPs but a scarcity of validated allosteric sites for RPTPs. The results of our study not only shed light on the regulatory role of RPTP-D2 domains, but also provide a potentially useful tool for the discovery of chemical probes targeting RPTPalpha and other RPTPs. |
