2vaf
From Proteopedia
(New page: 200px<br /> <applet load="2vaf" size="450" color="white" frame="true" align="right" spinBox="true" caption="2vaf, resolution 3.8Å" /> '''CRYSTAL STRUCTURE OF...) |
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caption="2vaf, resolution 3.8Å" /> | caption="2vaf, resolution 3.8Å" /> | ||
'''CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN'''<br /> | '''CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN'''<br /> | ||
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==Overview== | ==Overview== | ||
Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a, high-capacity, low-affinity Ca(2+)-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 Ca(2+)-binding capacity in, spite of the similarity of their secondary structures to that of the, wild-type hCSQ2. Light-scattering experiments indicate that the, Ca(2+)-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 Ca(2+) 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 Ca(2+). Although one of the non-pathological, mutants, T66A, shares characteristics with the wild-type, the other null, mutant, V76M, shows significantly altered Ca(2+)-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 Ca(2+)-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 Ca(2+)-binding capacity in, spite of the similarity of their secondary structures to that of the, wild-type hCSQ2. Light-scattering experiments indicate that the, Ca(2+)-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 Ca(2+) 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 Ca(2+). Although one of the non-pathological, mutants, T66A, shares characteristics with the wild-type, the other null, mutant, V76M, shows significantly altered Ca(2+)-binding and, polymerization behaviors, calling for careful reconsideration of its, status. | ||
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| - | ==Disease== | ||
| - | Known disease associated with this structure: Ventricular tachycardia, stress-induced polymorphic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114251 114251]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 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 superseeds the now removed PDB entry 2V0Q. Full crystallographic information is available from [http:// | + | 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 superseeds the now removed PDB entry 2V0Q. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VAF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: sarcoplasmic reticulum]] | [[Category: sarcoplasmic reticulum]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:51:37 2008'' |
Revision as of 10:51, 23 January 2008
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CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN
Overview
Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a, high-capacity, low-affinity Ca(2+)-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 Ca(2+)-binding capacity in, spite of the similarity of their secondary structures to that of the, wild-type hCSQ2. Light-scattering experiments indicate that the, Ca(2+)-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 Ca(2+) 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 Ca(2+). Although one of the non-pathological, mutants, T66A, shares characteristics with the wild-type, the other null, mutant, V76M, shows significantly altered Ca(2+)-binding and, polymerization behaviors, calling for careful reconsideration of its, status.
About this Structure
2VAF is a Single protein structure of sequence from Homo sapiens. This structure superseeds the now removed PDB entry 2V0Q. Full crystallographic information is available from OCA.
Reference
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 Aug 29;. PMID:17881003
Page seeded by OCA on Wed Jan 23 12:51:37 2008
Categories: Homo sapiens | Single protein | Campbell, C. | Kang, C. | Kemper, L. | Kim, E. | Milting, H. | Varsanyi, M. | Youn, B. | Calcium | Crystal structure human cardiac calsequestrin | Disease mutation | Glycoprotein | Metal-binding protein | Muscle protein | Polymorphism | Sarcoplasmic reticulum
