Journal article
Characterization of Human Cardiac Calsequestrin and its Deleterious Mutants
Journal of molecular biology, Vol.373(4), pp.1047-1057
2007
Handle:
https://hdl.handle.net/2376/110487
PMID: 17881003
Abstract
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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Details
- Title
- Characterization of Human Cardiac Calsequestrin and its Deleterious Mutants
- Creators
- EunJung Kim - School of Molecular Biosciences, Washington State University Pullman, WA 99164-4660, USABuhyun Youn - School of Molecular Biosciences, Washington State University Pullman, WA 99164-4660, USALenord Kemper - Department of Pharmaceutical Sciences, Washington State University Pullman, WA 99164-6534, USACait Campbell - School of Molecular Biosciences, Washington State University Pullman, WA 99164-4660, USAHendrik Milting - Herz- und Diabeteszentrum NRW, Klinik der Ruhr Universitaet Bochum Klinik der Ruhr-Universitat Bochum, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, 32545 Bad Oeynhausen, GermanyMagdolna Varsanyi - Institut für Physiologische Chemie, Ruhr Universität, D-44780 Bochum, GermanyChulHee Kang - School of Molecular Biosciences, Washington State University Pullman, WA 99164-4660, USA
- Publication Details
- Journal of molecular biology, Vol.373(4), pp.1047-1057
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900547279601842
- Language
- English
- Resource Type
- Journal article