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5wdi

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Revision as of 08:51, 30 September 2020

Structure of Human Sts-2 histidine phosphatase domain

Structural highlights

5wdi is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wdi"

@@ Line 1: / Line 1: @@
 ==Structure of Human Sts-2 histidine phosphatase domain==
-<StructureSection load='5wdi' size='340' side='right' caption='[[5wdi]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
+<StructureSection load='5wdi' size='340' side='right'caption='[[5wdi]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wdi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WDI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WDI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wdi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WDI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WDI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5wdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wdi OCA], [http://pdbe.org/5wdi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wdi RCSB], [http://www.ebi.ac.uk/pdbsum/5wdi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wdi ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5wdi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wdi OCA], [http://pdbe.org/5wdi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wdi RCSB], [http://www.ebi.ac.uk/pdbsum/5wdi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wdi ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Carpino, N]]
 [[Category: French, J B]]

5wdi

From Proteopedia

Revision as of 08:51, 30 September 2020

Structure of Human Sts-2 histidine phosphatase domain

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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