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2vaf

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[[Image:2vaf.jpg|left|200px]]<br /><applet load="2vaf" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2vaf, resolution 3.8&Aring;" />
 
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'''CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN'''<br />
 
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==Overview==
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==Crystal structure of Human Cardiac Calsequestrin==
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<StructureSection load='2vaf' size='340' side='right'caption='[[2vaf]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2vaf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2v0q 2v0q]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VAF FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.8&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vaf OCA], [https://pdbe.org/2vaf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vaf RCSB], [https://www.ebi.ac.uk/pdbsum/2vaf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vaf ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/CASQ2_HUMAN CASQ2_HUMAN] Defects in CASQ2 are the cause of catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) [MIM:[https://omim.org/entry/611938 611938]; also known as stress-induced polymorphic ventricular tachycardia (VTSIP). CPVT2 is an autosomal recessive form of arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death.<ref>PMID:17881003</ref> <ref>PMID:11704930</ref> <ref>PMID:15485681</ref> <ref>PMID:16908766</ref> <ref>PMID:18399795</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/CASQ2_HUMAN CASQ2_HUMAN] Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. The release of calcium bound to calsequestrin through a calcium release channel triggers muscle contraction. The skeletal muscle isoform (CASQ1) binds around 80 Ca(2+) ions, while the cardiac isoform (CASQ2) binds approximately 60 Ca(2+) ions.<ref>PMID:17881003</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/va/2vaf_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vaf ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a high-capacity, low-affinity Ca2+-binding protein in the sarcoplasmic reticulum, have been associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT). In order to understand the molecular mechanism and pathophysiological link between these CPVT-related missense mutations of hCSQ2 and the resulting arrhythmias, we generated three CPVT-causing mutants of hCSQ2 (R33Q, L167H, and D307H) and two non-pathological mutants (T66A and V76M) and investigated the effect of these mutations. In addition, we determined the crystal structure of the corresponding wild-type hCSQ2 to gain insight into the structural effects of those mutations. Our data show clearly that all three CPVT-related mutations lead to significant reduction in Ca2+-binding capacity in spite of the similarity of their secondary structures to that of the wild-type hCSQ2. Light-scattering experiments indicate that the Ca2+-dependent monomer-polymer transitions of the mutants are quite different, confirming that the linear polymerization behavior of CSQ is linked directly to its high-capacity Ca2+ binding. R33Q and D307H mutations result in a monomer that appears to be unable to form a properly oriented dimer. On the other hand, the L167H mutant has a disrupted hydrophobic core in domain II, resulting in high molecular aggregates, which cannot respond to Ca2+. Although one of the non-pathological mutants, T66A, shares characteristics with the wild-type, the other null mutant, V76M, shows significantly altered Ca2+-binding and polymerization behaviors, calling for careful reconsideration of its status.
Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a high-capacity, low-affinity Ca2+-binding protein in the sarcoplasmic reticulum, have been associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT). In order to understand the molecular mechanism and pathophysiological link between these CPVT-related missense mutations of hCSQ2 and the resulting arrhythmias, we generated three CPVT-causing mutants of hCSQ2 (R33Q, L167H, and D307H) and two non-pathological mutants (T66A and V76M) and investigated the effect of these mutations. In addition, we determined the crystal structure of the corresponding wild-type hCSQ2 to gain insight into the structural effects of those mutations. Our data show clearly that all three CPVT-related mutations lead to significant reduction in Ca2+-binding capacity in spite of the similarity of their secondary structures to that of the wild-type hCSQ2. Light-scattering experiments indicate that the Ca2+-dependent monomer-polymer transitions of the mutants are quite different, confirming that the linear polymerization behavior of CSQ is linked directly to its high-capacity Ca2+ binding. R33Q and D307H mutations result in a monomer that appears to be unable to form a properly oriented dimer. On the other hand, the L167H mutant has a disrupted hydrophobic core in domain II, resulting in high molecular aggregates, which cannot respond to Ca2+. Although one of the non-pathological mutants, T66A, shares characteristics with the wild-type, the other null mutant, V76M, shows significantly altered Ca2+-binding and polymerization behaviors, calling for careful reconsideration of its status.
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==Disease==
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Characterization of human cardiac calsequestrin and its deleterious mutants.,Kim E, Youn B, Kemper L, Campbell C, Milting H, Varsanyi M, Kang C J Mol Biol. 2007 Nov 2;373(4):1047-57. Epub 2007 Aug 29. PMID:17881003<ref>PMID:17881003</ref>
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Known disease associated with this structure: Ventricular tachycardia, stress-induced polymorphic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114251 114251]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2VAF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry 2V0Q. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VAF OCA].
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</div>
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<div class="pdbe-citations 2vaf" style="background-color:#fffaf0;"></div>
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==Reference==
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== References ==
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Characterization of human cardiac calsequestrin and its deleterious mutants., Kim E, Youn B, Kemper L, Campbell C, Milting H, Varsanyi M, Kang C, J Mol Biol. 2007 Nov 2;373(4):1047-57. Epub 2007 Aug 29. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17881003 17881003]
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Campbell, C.]]
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[[Category: Campbell C]]
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[[Category: Kang, C.]]
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[[Category: Kang C]]
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[[Category: Kemper, L.]]
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[[Category: Kemper L]]
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[[Category: Kim, E.]]
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[[Category: Kim E]]
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[[Category: Milting, H.]]
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[[Category: Milting H]]
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[[Category: Varsanyi, M.]]
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[[Category: Varsanyi M]]
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[[Category: Youn, B.]]
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[[Category: Youn B]]
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[[Category: calcium]]
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[[Category: crystal structure human cardiac calsequestrin]]
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[[Category: disease mutation]]
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[[Category: glycoprotein]]
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[[Category: metal-binding protein]]
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[[Category: muscle protein]]
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[[Category: polymorphism]]
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[[Category: sarcoplasmic reticulum]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:54:34 2008''
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Current revision

Crystal structure of Human Cardiac Calsequestrin

PDB ID 2vaf

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