Structural highlights
Function
[UBS3A_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, EGFR and PDGFRB, on the cell surface. Exhibits negligigle protein tyrosine phosphatase activity at neutral pH. May act as a dominant-negative regulator of UBASH3B-dependent dephosphorylation. May inhibit dynamin-dependent endocytic pathways by functionally sequestering dynamin via its SH3 domain.[1] [2] [3]
Publication Abstract from PubMed
The 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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kowanetz K, Crosetto N, Haglund K, Schmidt MH, Heldin CH, Dikic I. Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. J Biol Chem. 2004 Jul 30;279(31):32786-95. Epub 2004 May 24. PMID:15159412 doi:http://dx.doi.org/10.1074/jbc.M403759200
- ↑ Bertelsen V, Breen K, Sandvig K, Stang E, Madshus IH. The Cbl-interacting protein TULA inhibits dynamin-dependent endocytosis. Exp Cell Res. 2007 May 1;313(8):1696-709. Epub 2007 Feb 28. PMID:17382318 doi:http://dx.doi.org/10.1016/j.yexcr.2007.02.017
- ↑ Agrawal R, Carpino N, Tsygankov A. TULA proteins regulate activity of the protein tyrosine kinase Syk. J Cell Biochem. 2008 Jun 1;104(3):953-64. doi: 10.1002/jcb.21678. PMID:18189269 doi:http://dx.doi.org/10.1002/jcb.21678
- ↑ Zhou W, Yin Y, Weinheimer AS, Kaur N, Carpino N, French JB. Structural and functional characterization of the histidine phosphatase domains of human Sts-1 and Sts-2. Biochemistry. 2017 Jul 31. doi: 10.1021/acs.biochem.7b00638. PMID:28759203 doi:http://dx.doi.org/10.1021/acs.biochem.7b00638
