5vr6
Structure of Human Sts-1 histidine phosphatase domain with sulfate boundStructure of Human Sts-1 histidine phosphatase domain with sulfate bound
Structural highlights
FunctionUBS3B_HUMAN Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases. Promotes accumulation of activated target receptors, such as T-cell receptors and EGFR, on the cell surface. Exhibits tyrosine phosphatase activity toward several substrates including EGFR, FAK, SYK, and ZAP70. Down-regulates proteins that are dually modified by both protein tyrosine phosphorylation and ubiquitination.[1] [2] Publication Abstract from PubMedThe suppressor of T-cell signaling (Sts) proteins, Sts-1 and Sts-2, are homologous phosphatases that negatively regulate signaling pathways downstream of the T-cell receptor. Functional inactivation of Sts-1 and Sts-2 in a murine model leads to resistance to systemic infection by the opportunistic pathogen, C. albicans. This suggests that modulation of the host immune response by inhibiting Sts function may be a viable strategy to treat these deadly fungal pathogen infections. To better understand the molecular determinants of function and structure, we characterized the structure and steady-state kinetics of the histidine phosphatase domains of human Sts-1 (Sts-1HP) and Sts-2 (Sts-2HP). We solved the X-ray crystal structures of Sts-1HP, unliganded and in complex with sulfate to 2.5 A and 1.9 A, respectively, and the structure of Sts-2HP with sulfate to 2.4 A. The steady-state kinetic analysis shows, as expected, that Sts-1HP has a significantly higher phosphatase activity than that of Sts-2HP, and that the human and mouse proteins behave similarly. In addition, comparison of the phosphatase activity of full-length Sts-1 protein to Sts-1HP reveals similar kinetics, indicating that Sts-1HP is a functional surrogate for the native protein. We also tested known phosphatase inhibitors and identified that the SHP-1 inhibitor, PHPS1, is a potent inhibitor of Sts-1 (Ki of 1.05 +/- 0.15 microM). Finally, we demonstrated that human Sts-1 has robust phosphatase activity against the substrate, Zap-70, in a cell-based assay. Collectively, these data suggest that the human Sts proteins are druggable targets and provides a structural basis for future drug development efforts. Structural and functional characterization of the histidine phosphatase domains of human Sts-1 and Sts-2.,Zhou W, Yin Y, Weinheimer AS, Kaur N, Carpino N, French JB Biochemistry. 2017 Jul 31. doi: 10.1021/acs.biochem.7b00638. PMID:28759203[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||