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| | ==Crystal Structure of human vinculin head domain (residues 1-252) in complex with alpha-catenin (residues 277-382)== | | ==Crystal Structure of human vinculin head domain (residues 1-252) in complex with alpha-catenin (residues 277-382)== |
| - | <StructureSection load='4ehp' size='340' side='right' caption='[[4ehp]], [[Resolution|resolution]] 2.66Å' scene=''> | + | <StructureSection load='4ehp' size='340' side='right'caption='[[4ehp]], [[Resolution|resolution]] 2.66Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ehp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EHP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EHP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ehp]] 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=4EHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EHP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></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]] 2.66Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tr2|1tr2]], [[1rke|1rke]], [[4dj9|4dj9]], [[3tj5|3tj5]], [[1syq|1syq]], [[1rkc|1rkc]], [[2gww|2gww]], [[3rf3|3rf3]], [[3s90|3s90]], [[3tj6|3tj6]], [[2hsq|2hsq]], [[2ibf|2ibf]], [[1ydi|1ydi]], [[3h2u|3h2u]], [[3h2v|3h2v]], [[3myi|3myi]], [[3smz|3smz]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VCL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), CTNNA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4ehp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ehp OCA], [https://pdbe.org/4ehp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ehp RCSB], [https://www.ebi.ac.uk/pdbsum/4ehp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ehp ProSAT]</span></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=4ehp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ehp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ehp RCSB], [http://www.ebi.ac.uk/pdbsum/4ehp PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/VINC_HUMAN VINC_HUMAN]] Defects in VCL are the cause of cardiomyopathy dilated type 1W (CMD1W) [MIM:[http://omim.org/entry/611407 611407]]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:11815424</ref> <ref>PMID:16236538</ref> Defects in VCL are the cause of familial hypertrophic cardiomyopathy type 15 (CMH15) [MIM:[http://omim.org/entry/613255 613255]]. It is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:16712796</ref> | + | [https://www.uniprot.org/uniprot/VINC_HUMAN VINC_HUMAN] Defects in VCL are the cause of cardiomyopathy dilated type 1W (CMD1W) [MIM:[https://omim.org/entry/611407 611407]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:11815424</ref> <ref>PMID:16236538</ref> Defects in VCL are the cause of familial hypertrophic cardiomyopathy type 15 (CMH15) [MIM:[https://omim.org/entry/613255 613255]. It is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:16712796</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VINC_HUMAN VINC_HUMAN]] Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. Regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion.<ref>PMID:20484056</ref> [[http://www.uniprot.org/uniprot/CTNA1_HUMAN CTNA1_HUMAN]] Associates with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Can associate with both E- and N-cadherins. Originally believed to be a stable component of E-cadherin/catenin adhesion complexes and to mediate the linkage of cadherins to the actin cytoskeleton at adherens junctions. In contrast, cortical actin was found to be much more dynamic than E-cadherin/catenin complexes and CTNNA1 was shown not to bind to F-actin when assembled in the complex suggesting a different linkage between actin and adherens junctions components. The homodimeric form may regulate actin filament assembly and inhibit actin branching by competing with the Arp2/3 complex for binding to actin filaments. May play a crucial role in cell differentiation. | + | [https://www.uniprot.org/uniprot/VINC_HUMAN VINC_HUMAN] Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. Regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion.<ref>PMID:20484056</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4ehp" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Catenin|Catenin]] | + | *[[Catenin 3D structures|Catenin 3D structures]] |
| - | *[[Vinculin|Vinculin]] | + | *[[Vinculin 3D structures|Vinculin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Izard, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Rangarajan, E S]] | + | [[Category: Izard T]] |
| - | [[Category: Adherens junction]] | + | [[Category: Rangarajan ES]] |
| - | [[Category: Cell adhesion]]
| + | |
| - | [[Category: Helix bundle]]
| + | |
| - | [[Category: Vinculin binding domain]]
| + | |
| - | [[Category: Vinculin binding site]]
| + | |
| Structural highlights
Disease
VINC_HUMAN Defects in VCL are the cause of cardiomyopathy dilated type 1W (CMD1W) [MIM:611407. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] [2] Defects in VCL are the cause of familial hypertrophic cardiomyopathy type 15 (CMH15) [MIM:613255. It is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[3]
Function
VINC_HUMAN Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. Regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion.[4]
Publication Abstract from PubMed
Adherens junctions (AJs) are essential for cell-cell contacts, morphogenesis, and the development of all higher eukaryotes. AJs are formed by calcium-dependent homotypic interactions of the ectodomains of single membrane-pass cadherin family receptors. These homotypic interactions in turn promote binding of the intracellular cytoplasmic tail domains of cadherin receptors with beta-catenin, a multifunctional protein that plays roles in both transcription and AJs. The cadherin receptor-beta-catenin complex binds to the cytoskeletal protein alpha-catenin, which is essential for both the formation and the stabilization of these junctions. Precisely how alpha-catenin contributes to the formation and stabilization of AJs is hotly debated, although the latter is thought to involve its interactions with the cytoskeletal protein vinculin. Here we report the crystal structure of the vinculin binding domain (VBD) of alpha-catenin in complex with the vinculin head domain (Vh1). This structure reveals that alpha-catenin is in a unique unfurled mode allowing dimer formation when bound to vinculin. Finally, binding studies suggest that vinculin must be in an activated state to bind to alpha-catenin and that this interaction is stabilized by the formation of a ternary alpha-catenin-vinculin-F-actin complex, which can be formed via the F-actin binding domain of either protein. We propose a feed-forward model whereby alpha-catenin-vinculin interactions promote their binding to the actin cytoskeleton to stabilize AJs.
The cytoskeletal protein alpha-catenin unfurls upon binding to vinculin.,Rangarajan ES, Izard T J Biol Chem. 2012 May 25;287(22):18492-9. Epub 2012 Apr 6. PMID:22493458[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Olson TM, Illenberger S, Kishimoto NY, Huttelmaier S, Keating MT, Jockusch BM. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002 Jan 29;105(4):431-7. PMID:11815424
- ↑ Vasile VC, Will ML, Ommen SR, Edwards WD, Olson TM, Ackerman MJ. Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. Mol Genet Metab. 2006 Feb;87(2):169-74. Epub 2005 Oct 19. PMID:16236538 doi:S1096-7192(05)00258-1
- ↑ Vasile VC, Ommen SR, Edwards WD, Ackerman MJ. A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2006 Jul 7;345(3):998-1003. Epub 2006 May 4. PMID:16712796 doi:S0006-291X(06)00981-8
- ↑ Le Clainche C, Dwivedi SP, Didry D, Carlier MF. Vinculin is a dually regulated actin filament barbed end-capping and side-binding protein. J Biol Chem. 2010 Jul 23;285(30):23420-32. doi: 10.1074/jbc.M110.102830. Epub, 2010 May 18. PMID:20484056 doi:10.1074/jbc.M110.102830
- ↑ Rangarajan ES, Izard T. The cytoskeletal protein alpha-catenin unfurls upon binding to vinculin. J Biol Chem. 2012 May 25;287(22):18492-9. Epub 2012 Apr 6. PMID:22493458 doi:10.1074/jbc.M112.351023
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