2vaf

From Proteopedia

Revision as of 16:44, 20 March 2008

CRYSTAL STRUCTURE OF HUMAN CARDIAC CALSEQUESTRIN

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

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