Allosteric Modulation of SERCA Pumps in Health and Disease: Structural Dynamics, Posttranslational Modifications, and Therapeutic Potential.

Abstract

Sarco/endoplasmic reticulum (SR/ER) Ca²⁺-ATPase (SERCA) pumps are ubiquitous membrane proteins in all eukaryotic cells, playing a central role in maintaining intracellular calcium homeostasis by re-sequestering Ca²⁺ 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, Ca²⁺ 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.