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| | ==Structure of Human Sts-1 histidine phosphatase domain== | | ==Structure of Human Sts-1 histidine phosphatase domain== |
| - | <StructureSection load='5w5g' size='340' side='right' caption='[[5w5g]], [[Resolution|resolution]] 2.48Å' scene=''> | + | <StructureSection load='5w5g' size='340' side='right'caption='[[5w5g]], [[Resolution|resolution]] 2.48Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5w5g]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W5G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W5G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5w5g]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W5G FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.48Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5w5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w5g OCA], [http://pdbe.org/5w5g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w5g RCSB], [http://www.ebi.ac.uk/pdbsum/5w5g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w5g ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5w5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w5g OCA], [https://pdbe.org/5w5g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w5g RCSB], [https://www.ebi.ac.uk/pdbsum/5w5g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w5g ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBS3B_HUMAN UBS3B_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.<ref>PMID:15159412</ref> <ref>PMID:17880946</ref> | + | [https://www.uniprot.org/uniprot/UBS3B_HUMAN UBS3B_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.<ref>PMID:15159412</ref> <ref>PMID:17880946</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Carpino, N]] | + | [[Category: Large Structures]] |
| - | [[Category: French, J B]] | + | [[Category: Carpino N]] |
| - | [[Category: Kaur, N]] | + | [[Category: French JB]] |
| - | [[Category: Weinheimer, A W]] | + | [[Category: Kaur N]] |
| - | [[Category: Yin, Y]] | + | [[Category: Weinheimer AW]] |
| - | [[Category: Zhou, W]] | + | [[Category: Yin Y]] |
| - | [[Category: Histidine phosphatase]]
| + | [[Category: Zhou W]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Protein tyrosine phosphatase]]
| + | |
| - | [[Category: T-cell receptor]]
| + | |
| - | [[Category: Zap-70]]
| + | |
| Structural highlights
Function
UBS3B_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 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[3]
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
- ↑ Raguz J, Wagner S, Dikic I, Hoeller D. Suppressor of T-cell receptor signalling 1 and 2 differentially regulate endocytosis and signalling of receptor tyrosine kinases. FEBS Lett. 2007 Oct 2;581(24):4767-72. Epub 2007 Sep 11. PMID:17880946 doi:http://dx.doi.org/10.1016/j.febslet.2007.08.077
- ↑ 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
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