2vaf
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Mutations of conserved residues of human cardiac calsequestrin (hCSQ2), a | + | 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== | ||
| + | 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 | + | 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]. |
==Reference== | ==Reference== | ||
| - | Characterization of | + | 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] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: sarcoplasmic reticulum]] | [[Category: sarcoplasmic reticulum]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:54:34 2008'' |
Revision as of 16:54, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN
Contents |
Overview
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.
Disease
Known disease associated with this structure: Ventricular tachycardia, stress-induced polymorphic OMIM:[114251]
About this Structure
2VAF is a Single protein structure of sequence from Homo sapiens. This structure supersedes 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 Nov 2;373(4):1047-57. Epub 2007 Aug 29. PMID:17881003
Page seeded by OCA on Thu Feb 21 18:54:34 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
