6uzt: Difference between revisions
New page: '''Unreleased structure''' The entry 6uzt is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal Structure of RPTP alpha== | ||
<StructureSection load='6uzt' size='340' side='right'caption='[[6uzt]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6uzt]] is a 2 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=6UZT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UZT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</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=6uzt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uzt OCA], [https://pdbe.org/6uzt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uzt RCSB], [https://www.ebi.ac.uk/pdbsum/6uzt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uzt ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PTPRA_HUMAN PTPRA_HUMAN] Tyrosine protein phosphatase which is involved in integrin-mediated focal adhesion formation (By similarity). Following integrin engagement, specifically recruits BCAR3, BCAR1 and CRK to focal adhesions thereby promoting SRC-mediated phosphorylation of BRAC1 and the subsequent activation of PAK and small GTPase RAC1 and CDC42 (By similarity).[UniProtKB:P18052] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Receptor-type protein tyrosine phosphatase alpha (RPTPalpha) 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 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 RPTPalpha-D2 or other RPTP-D2 domains. Here, we solved the 1.8 A resolution crystal structure of the cytoplasmic region of RPTPalpha, 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 RPTPalpha variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTPalpha phosphatase activity and identified a P405FTP408 motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTPalpha 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 RPTPalpha and other RPTPs. | |||
RPTPalpha phosphatase activity is allosterically regulated by the membrane-distal catalytic domain.,Wen Y, Yang S, Wakabayashi K, Svensson MND, Stanford SM, Santelli E, Bottini N J Biol Chem. 2020 Mar 5. pii: RA119.011808. doi: 10.1074/jbc.RA119.011808. PMID:32139509<ref>PMID:32139509</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6uzt" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bottini N]] | |||
[[Category: Santelli E]] | |||
[[Category: Stanford SM]] | |||
[[Category: Svensson MND]] | |||
[[Category: Wen Y]] | |||
[[Category: Yang S]] | |||
Latest revision as of 11:01, 11 October 2023
Crystal Structure of RPTP alphaCrystal Structure of RPTP alpha
Structural highlights
FunctionPTPRA_HUMAN Tyrosine protein phosphatase which is involved in integrin-mediated focal adhesion formation (By similarity). Following integrin engagement, specifically recruits BCAR3, BCAR1 and CRK to focal adhesions thereby promoting SRC-mediated phosphorylation of BRAC1 and the subsequent activation of PAK and small GTPase RAC1 and CDC42 (By similarity).[UniProtKB:P18052] Publication Abstract from PubMedReceptor-type protein tyrosine phosphatase alpha (RPTPalpha) 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 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 RPTPalpha-D2 or other RPTP-D2 domains. Here, we solved the 1.8 A resolution crystal structure of the cytoplasmic region of RPTPalpha, 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 RPTPalpha variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTPalpha phosphatase activity and identified a P405FTP408 motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTPalpha 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 RPTPalpha and other RPTPs. RPTPalpha phosphatase activity is allosterically regulated by the membrane-distal catalytic domain.,Wen Y, Yang S, Wakabayashi K, Svensson MND, Stanford SM, Santelli E, Bottini N J Biol Chem. 2020 Mar 5. pii: RA119.011808. doi: 10.1074/jbc.RA119.011808. PMID:32139509[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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