6UZT
Crystal Structure of RPTP alpha
Summary for 6UZT
| Entry DOI | 10.2210/pdb6uzt/pdb |
| Descriptor | Receptor-type tyrosine-protein phosphatase alpha (2 entities in total) |
| Functional Keywords | protein tyrosine phosphatase, enzyme, hydrolase, alpha/beta protein, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 139220.27 |
| Authors | Santelli, E.,Wen, Y.,Yang, S.,Svensson, M.N.D.,Stanford, S.M.,Bottini, N. (deposition date: 2019-11-15, release date: 2020-03-18, Last modification date: 2023-10-11) |
| Primary citation | Wen, Y.,Yang, S.,Wakabayashi, K.,Svensson, M.N.D.,Stanford, S.M.,Santelli, E.,Bottini, N. RPTP alpha phosphatase activity is allosterically regulated by the membrane-distal catalytic domain. J.Biol.Chem., 295:4923-4936, 2020 Cited by PubMed Abstract: Receptor-type protein tyrosine phosphatase α (RPTPα) 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 RPTPα-D2 or other RPTP-D2 domains. Here, we solved the 1.8 Å resolution crystal structure of the cytoplasmic region of RPTPα, 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 RPTPα variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTPα phosphatase activity and identified a PFTP motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTPα 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 RPTPα and other RPTPs. PubMed: 32139509DOI: 10.1074/jbc.RA119.011808 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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