Abstract
The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the “regulins”. Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA—formed by transmembrane helices M2, M6, and M9—can result in distinct functional outcomes.
Highlights
Background on sarco-endoplasmic reticulum calcium ATPase (SERCA) RegulationThe sarco-endoplasmic reticulum calcium pump is ubiquitously expressed in the SR/ER membranes of all eukaryotic cells and tissues
In addition to the displacement of PLN, we have shown that dwarf open reading frame (DWORF) is a direct activator of SERCA even in the absence of PLN [25]
Like DWORF, MLN primarily interacts with transmembrane segments M2 and M9 of SERCA and it makes a single contact with M6 (Table 2)
Summary
The sarco-endoplasmic reticulum calcium pump ( known as Ca2+-ATPase or SERCA) is ubiquitously expressed in the SR/ER membranes of all eukaryotic cells and tissues. Like DWORF, MLN primarily interacts with transmembrane segments M2 and M9 of SERCA and it makes a single contact with M6 (Table 2) This offers an explanation for why MLN does not alter the apparent calcium affinity of SERCA since inhibition of SERCA by PLN and SLN involves substantial interactions with transmembrane segment M6 of SERCA. There are no current physiological or disease-associated roles for ELN or ALN, though the identification of SERCA regulators in non-muscle tissues is an exciting development in our understanding of the regulation of calcium homeostasis in all cells Like their muscle-specific counterparts, ELN and ALN localize to the ER membrane and their helical transmembrane domains are thought to interact with the inhibitory groove of SERCA. Like PLN and SLN, ALN makes contacts with the transmembrane segment M6 of SERCA (Table 2), which offers an explanation for why ALN alters the apparent calcium affinity of SERCA in a manner similar to PLN and SLN
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