Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
Laboratory of Molecular Cardiology, IRCCS ICS Maugeri, 27100 Pavia, Italy.
Biomolecules. 2023 Nov 23;13(12):1693. doi: 10.3390/biom13121693.
Calsequestrin (CASQ) is a key intra-sarcoplasmic reticulum Ca-handling protein that plays a pivotal role in the contraction of cardiac and skeletal muscles. Its Ca-dependent polymerization dynamics shape the translation of electric excitation signals to the Ca-induced contraction of the actin-myosin architecture. Mutations in CASQ are linked to life-threatening pathological conditions, including tubular aggregate myopathy, malignant hyperthermia, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The variability in the penetrance of these phenotypes and the lack of a clear understanding of the disease mechanisms associated with CASQ mutations pose a major challenge to the development of effective therapeutic strategies. In vitro studies have mainly focused on the polymerization and Ca-buffering properties of CASQ but have provided little insight into the complex interplay of structural and functional changes that underlie disease. In this review, the biochemical and structural natures of CASQ are explored in-depth, while emphasizing their direct and indirect consequences for muscle Ca physiology. We propose a novel functional classification of CASQ pathological missense mutations based on the structural stability of the monomer, dimer, or linear polymer conformation. We also highlight emerging similarities between polymeric CASQ and polyelectrolyte systems, emphasizing the potential for the use of this paradigm to guide further research.
钙结合蛋白（CASQ）是一种关键的肌质网内钙处理蛋白，在心脏和骨骼肌的收缩中起着关键作用。其钙依赖性聚合动力学将电兴奋信号的转换为肌动球蛋白结构的钙诱导收缩。CASQ 突变与危及生命的病理状况有关，包括管状聚集性肌病、恶性高热和儿茶酚胺多形性室性心动过速（CPVT）。这些表型的外显率的可变性和对与 CASQ 突变相关的疾病机制缺乏清晰的理解，对有效治疗策略的发展构成了重大挑战。体外研究主要集中在 CASQ 的聚合和钙缓冲特性上，但对导致疾病的结构和功能变化的复杂相互作用提供的见解甚少。在这篇综述中，深入探讨了 CASQ 的生化和结构性质，同时强调了它们对肌肉钙生理学的直接和间接影响。我们根据单体、二聚体或线性聚合物构象的结构稳定性，提出了一种新的 CASQ 病理性错义突变的功能分类。我们还强调了聚合 CASQ 与聚电解质系统之间的新出现的相似性，强调了使用这种范例来指导进一步研究的潜力。
