Viskupicova Jana, Espinoza-Fonseca L Michel
Centre of Experimental Medicine, Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, 84104 Bratislava, Slovakia.
Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
J Mol Biol. 2025 May 9:169200. doi: 10.1016/j.jmb.2025.169200.
Sarco/endoplasmic reticulum (SR/ER) Ca-ATPase (SERCA) pumps are ubiquitous membrane proteins in all eukaryotic cells, playing a central role in maintaining intracellular calcium homeostasis by re-sequestering Ca ions from the cytosol into the SR/ER at the expense of ATP hydrolysis. SERCA pumps are well-characterized components of the calcium transport machinery in the cell, playing a role in various physiological processes, including muscle contraction, energy metabolism, secretion exocytosis, gene expression, synaptic transmission, cell survival, and fertilization. Allosteric regulation of SERCA pumps plays a key role in health and disease, and modulation of the SERCA pumps has emerged as a therapeutic approach for the treatment of cardiovascular, muscular, metabolic, and neurodegenerative disorders. In this review, we provide a comprehensive overview of the structural dynamics underlying allosteric modulation of SERCA, focusing on the effects of endogenous regulatory proteins, Ca ions, ATP, and small molecules. We also examine in detail the role of posttranslational modifications as allosteric modulators of SERCA function, focusing on the oxidative modifications S-glutathionylation, S-nitrosylation, tyrosine nitration, and carbonylation, and non-oxidative modifications that include SUMOylation, acetylation, O-GlcNAcylation, phosphorylation, and ubiquitination. Finally, we discuss the therapeutic potential and challenges of allosteric modulation of SERCA pumps, including the design of small-molecule effectors, microRNA-based interventions, and targeted strategies that modulate SERCA posttranslational regulation. Overall, this review aims to bridge the gap between the mechanisms underlying allosteric modulation of SERCA and the translation of basic science discoveries into effective therapies targeting SERCA pumps.
肌浆网/内质网（SR/ER）钙-ATP酶（SERCA）泵是所有真核细胞中普遍存在的膜蛋白，通过以ATP水解为代价将钙离子从细胞质重新隔离到SR/ER中，在维持细胞内钙稳态方面发挥核心作用。SERCA泵是细胞钙转运机制中特征明确的组成部分，在各种生理过程中发挥作用，包括肌肉收缩、能量代谢、分泌性胞吐作用、基因表达、突触传递、细胞存活和受精。SERCA泵的变构调节在健康和疾病中起关键作用，对SERCA泵的调节已成为治疗心血管、肌肉、代谢和神经退行性疾病的一种治疗方法。在本综述中，我们全面概述了SERCA变构调节的结构动力学，重点关注内源性调节蛋白、钙离子、ATP和小分子的作用。我们还详细研究了翻译后修饰作为SERCA功能变构调节剂的作用，重点关注氧化修饰S-谷胱甘肽化、S-亚硝基化、酪氨酸硝化和羰基化，以及包括SUMO化、乙酰化、O-连接N-乙酰葡糖胺化、磷酸化和泛素化在内的非氧化修饰。最后，我们讨论了SERCA泵变构调节的治疗潜力和挑战，包括小分子效应物的设计、基于微小RNA的干预措施以及调节SERCA翻译后调节的靶向策略。总体而言，本综述旨在弥合SERCA变构调节机制与将基础科学发现转化为针对SERCA泵的有效疗法之间的差距。
