5l0g
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Human metavinculin MVt Q971R, R975D, T978R mutant (residues 959-1134) in complex with PIP2== | |
| + | <StructureSection load='5l0g' size='340' side='right' caption='[[5l0g]], [[Resolution|resolution]] 3.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5l0g]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L0G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L0G FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PIO:[(2R)-2-OCTANOYLOXY-3-[OXIDANYL-[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIS(OXIDANYL)-4,5-DIPHOSPHONOOXY-CYCLOHEXYL]OXY-PHOSPHORYL]OXY-PROPYL]+OCTANOATE'>PIO</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=5l0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l0g OCA], [http://pdbe.org/5l0g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l0g RCSB], [http://www.ebi.ac.uk/pdbsum/5l0g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l0g ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == 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> | ||
| + | == 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The main cause of death globally remains debilitating heart conditions, such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which are often due to mutations of specific components of adhesion complexes. Vinculin regulates these complexes and plays essential roles in intercalated discs that are necessary for muscle cell function and coordinated movement and in the development and function of the heart. Humans bearing familial or sporadic mutations in vinculin suffer from chronic, progressively debilitating DCM that ultimately leads to cardiac failure and death, whereas autosomal dominant mutations in vinculin can also provoke HCM, causing acute cardiac failure. The DCM/HCM-associated mutants of vinculin occur in the 68-residue insert unique to the muscle-specific, alternatively spliced isoform of vinculin, termed metavinculin (MV). Contrary to studies that suggested that phosphoinositol-4,5-bisphosphate (PIP2) only induces vinculin homodimers, which are asymmetric, we show that phospholipid binding results in a domain-swapped symmetric MV dimer via a quasi-equivalent interface compared with vinculin involving R975. Although one of the two PIP2 binding sites is preserved, the symmetric MV dimer that bridges two PIP2 molecules differs from the asymmetric vinculin dimer that bridges only one PIP2 Unlike vinculin, wild-type MV and the DCM/HCM-associated R975W mutant bind PIP2 in their inactive conformations, and R975W MV fails to dimerize. Mutating selective vinculin residues to their corresponding MV residues, or vice versa, switches the isoform's dimeric constellation and lipid binding site. Collectively, our data suggest that MV homodimerization modulates microfilament attachment at muscular adhesion sites and furthers our understanding of MV-mediated cardiac remodeling. | ||
| - | + | Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization.,Chinthalapudi K, Rangarajan ES, Brown DT, Izard T Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9539-44. doi:, 10.1073/pnas.1600702113. Epub 2016 Aug 8. PMID:27503891<ref>PMID:27503891</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 5l0g" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Chinthalapudi, K]] | [[Category: Chinthalapudi, K]] | ||
[[Category: Izard, T]] | [[Category: Izard, T]] | ||
| + | [[Category: 5-helix bundle]] | ||
| + | [[Category: Cell adhesion]] | ||
| + | [[Category: Cytoskelatal protein]] | ||
| + | [[Category: Phospholipid]] | ||
| + | [[Category: Structural protein]] | ||
Revision as of 05:24, 9 September 2016
Human metavinculin MVt Q971R, R975D, T978R mutant (residues 959-1134) in complex with PIP2
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