ArticleThe Journal of biological chemistry2010
The catecholaminergic polymorphic ventricular tachycardia mutation R33Q disrupts the N-terminal structural motif that regulates reversible calsequestrin polymerization.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms ofCirculation · 2020Trial
- The emerging role of calsequestrin 2: from calcium sensor and modulator to arrhythmia driver.Journal of physiology and biochemistry · 2026Review
- Cardiac Channelopathies: Clinical Diagnosis and Promising Therapeutics.Journal of the American Heart Association · 2025Review
- Deep-time gene expression shift reveals an ancient change in avian muscle phenotypes.PLoS genetics · 2025Article
- The Structural-Functional Crosstalk of the Calsequestrin System: Insights and Pathological Implications.Biomolecules · 2023Review
- The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias.Biophysical reviews · 2022Review
- Calsequestrin, a key protein in striated muscle health and disease.Journal of muscle research and cell motility · 2021Review
- The structure of a calsequestrin filament reveals mechanisms of familial arrhythmia.Nature structural & molecular biology · 2020Article
- Phylogenetic and biochemical analysis of calsequestrin structure and association of its variants with cardiac disorders.Scientific reports · 2020Article
- Calcium Handling Defects and Cardiac Arrhythmia Syndromes.Frontiers in pharmacology · 2020Review
- Article
- Compound heterozygous CASQ2 mutations and long-term course of catecholaminergic polymorphic ventricular tachycardia.Molecular genetics & genomic medicine · 2017Article
- The C-terminal calcium-sensitive disordered motifs regulate isoform-specific polymerization characteristics of calsequestrin.Biopolymers · 2015Article
- Molecular mechanisms of disease-causing missense mutations.Journal of molecular biology · 2013Review
- Functional interaction between calsequestrin and ryanodine receptor in the heart.Cellular and molecular life sciences : CMLS · 2013Review
- Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization.Molecular bioSystems · 2013Article
- Inherited calcium channelopathies in the pathophysiology of arrhythmias.Nature reviews. Cardiology · 2012Review
- Calsequestrin mutations and catecholaminergic polymorphic ventricular tachycardia.Pediatric cardiology · 2012Review
- Calsequestrin 2 and arrhythmias.American journal of physiology. Heart and circulatory physiology · 2012Review
- Functional and structural characterization of a eurytolerant calsequestrin from the intertidal teleost Fundulus heteroclitus.PloS one · 2012Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Calsequestrin undergoes dynamic polymerization with increasing calcium concentration by front-to-front dimerization and back-to-back packing, forming wire-shaped structures. A recent finding that point mutation R33Q leads to lethal catecholaminergic polymorphic ventricular tachycardia (CPVT) implies a crucial role for the N terminus. In this study, we demonstrate that this mutation resides in a highly conserved alternately charged residue cluster (DGKDR; cluster 1) in the N-terminal end of calsequestrin. We further show that this cluster configures itself as a ring system and that the dipolar arrangement within the cluster brings about a critical conformational flip of Lys(31)-Asp(32) essential for dimer stabilization by formation of a H-bond network. We additionally show that Ca(2+)-induced calsequestrin aggregation is nonlinear and reversible and can regain the native conformation by Ca(2+) chelation with EGTA. This study suggests that cluster 1 works as a molecular switch and governs the bidirectional transition between the CASQ2 monomer and dimer. We further demonstrate that mutations disrupting the alternating charge pattern of the cluster, including R33Q, impair Ca(2+)-CASQ2 interaction, leading to altered polymerization-depolymerization dynamics. This study provides new mechanistic insight into the functional effects of the R33Q mutation and its potential role in CPVT.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.