2loz

From Proteopedia

(Difference between revisions)

Revision as of 09:07, 14 June 2023

The novel binding mode of DLC1 and Tensin2 PTB domain

Structural highlights

2loz is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TENS2_HUMAN Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin (PubMed:15817639, PubMed:23401856). Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain (PubMed:30092354). In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy (PubMed:23401856, PubMed:30092354). Negatively regulates PI3K-AKT pathway activation (PubMed:15817639, PubMed:23401856, PubMed:30092354). Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex (PubMed:28955049). Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria (PubMed:28955049). Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix (PubMed:20069572).[UniProtKB:Q8CGB6]^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.

Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode.,Chen L, Liu C, Ko FC, Xu N, Ng IO, Yam JW, Zhu G J Biol Chem. 2012 Jul 27;287(31):26104-14. doi: 10.1074/jbc.M112.360206. Epub, 2012 May 29. PMID:22645138^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hafizi S, Ibraimi F, Dahlback B. C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. FASEB J. 2005 Jun;19(8):971-3. Epub 2005 Apr 7. PMID:15817639 doi:http://dx.doi.org/10.1096/fj.04-2532fje
↑ Clark K, Howe JD, Pullar CE, Green JA, Artym VV, Yamada KM, Critchley DR. Tensin 2 modulates cell contractility in 3D collagen gels through the RhoGAP DLC1. J Cell Biochem. 2010 Mar 1;109(4):808-17. PMID:20069572 doi:10.1002/jcb.22460
↑ Koh A, Lee MN, Yang YR, Jeong H, Ghim J, Noh J, Kim J, Ryu D, Park S, Song P, Koo SH, Leslie NR, Berggren PO, Choi JH, Suh PG, Ryu SH. C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1 (IRS-1), regulating IRS-1 stability and muscle atrophy. Mol Cell Biol. 2013 Apr;33(8):1608-20. PMID:23401856 doi:10.1128/MCB.01447-12
↑ Shih YP, Sun P, Wang A, Lo SH. Tensin1 positively regulates RhoA activity through its interaction with DLC1. Biochim Biophys Acta. 2015 Dec;1853(12):3258-65. PMID:26427649 doi:10.1016/j.bbamcr.2015.09.028
↑ Lee J, Koh A, Jeong H, Kim E, Ha TS, Saleem MA, Ryu SH. C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation. Sci Rep. 2017 Sep 27;7(1):12346. PMID:28955049 doi:10.1038/s41598-017-12382-8
↑ Kim E, Kim DH, Singaram I, Jeong H, Koh A, Lee J, Cho W, Ryu SH. Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain. Cell Signal. 2018 Nov;51:130-138. PMID:30092354 doi:10.1016/j.cellsig.2018.07.009
↑ Chen L, Liu C, Ko FC, Xu N, Ng IO, Yam JW, Zhu G. Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode. J Biol Chem. 2012 Jul 27;287(31):26104-14. doi: 10.1074/jbc.M112.360206. Epub, 2012 May 29. PMID:22645138 doi:http://dx.doi.org/10.1074/jbc.M112.360206

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/2loz"

Categories: Homo sapiens | Large Structures | Chen L | Liu C | Zhu G

@@ Line 1: / Line 1: @@
 ==The novel binding mode of DLC1 and Tensin2 PTB domain==
-<StructureSection load='2loz' size='340' side='right'caption='[[2loz]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
+<StructureSection load='2loz' size='340' side='right'caption='[[2loz]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2loz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LOZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LOZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2loz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LOZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LOZ FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TENC1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DLC1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</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=2loz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2loz OCA], [https://pdbe.org/2loz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2loz RCSB], [https://www.ebi.ac.uk/pdbsum/2loz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2loz 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=2loz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2loz OCA], [https://pdbe.org/2loz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2loz RCSB], [https://www.ebi.ac.uk/pdbsum/2loz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2loz ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/TENC1_HUMAN TENC1_HUMAN]] Regulates cell motility and proliferation. May have phosphatase activity. Reduces AKT1 phosphorylation. Lowers AKT1 kinase activity and interferes with AKT1 signaling.<ref>PMID:15817639</ref>  [[https://www.uniprot.org/uniprot/RHG07_HUMAN RHG07_HUMAN]] Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling. This induces morphological changes and detachment through cytoskeletal reorganization, playing a critical role in biological processes such as cell migration and proliferation. Also functions in vivo as an activator of the phospholipase PLCD1. Active DLC1 increases cell migration velocity but reduces directionality.<ref>PMID:18786931</ref> <ref>PMID:19170769</ref> <ref>PMID:19710422</ref>
+[https://www.uniprot.org/uniprot/TENS2_HUMAN TENS2_HUMAN] Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin (PubMed:15817639, PubMed:23401856). Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain (PubMed:30092354). In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy (PubMed:23401856, PubMed:30092354). Negatively regulates PI3K-AKT pathway activation (PubMed:15817639, PubMed:23401856, PubMed:30092354). Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex (PubMed:28955049). Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria (PubMed:28955049). Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix (PubMed:20069572).[UniProtKB:Q8CGB6]<ref>PMID:15817639</ref> <ref>PMID:20069572</ref> <ref>PMID:23401856</ref> <ref>PMID:26427649</ref> <ref>PMID:28955049</ref> <ref>PMID:30092354</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chen, L]]
+[[Category: Chen L]]
-[[Category: Liu, C]]
+[[Category: Liu C]]
-[[Category: Zhu, G]]
+[[Category: Zhu G]]
-[[Category: Dlc1]]
-[[Category: Hydrolase-hydrolase activator complex]]
-[[Category: Ptb]]

2loz

From Proteopedia

Revision as of 09:07, 14 June 2023

The novel binding mode of DLC1 and Tensin2 PTB domain

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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