6uzt
Crystal Structure of RPTP alpha
Structural highlights
FunctionPTPRA_HUMAN Tyrosine protein phosphatase which is involved in integrin-mediated focal adhesion formation (By similarity). Following integrin engagement, specifically recruits BCAR3, BCAR1 and CRK to focal adhesions thereby promoting SRC-mediated phosphorylation of BRAC1 and the subsequent activation of PAK and small GTPase RAC1 and CDC42 (By similarity).[UniProtKB:P18052] Publication Abstract from PubMedReceptor-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 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 P405FTP408 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. RPTPalpha phosphatase activity is allosterically regulated by the membrane-distal catalytic domain.,Wen Y, Yang S, Wakabayashi K, Svensson MND, Stanford SM, Santelli E, Bottini N J Biol Chem. 2020 Mar 5. pii: RA119.011808. doi: 10.1074/jbc.RA119.011808. PMID:32139509[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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