Homologous cardiac calcium pump regulators phospholamban and sarcolipin adopt distinct oligomeric states in the membrane.

Autor:	Liu AY; Center for Arrhythmia Research, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.; McKetta Department of Chemical Engineering, The University of Texas, Austin, TX 78712, USA., Aguayo-Ortiz R; Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico., Guerrero-Serna G; Center for Arrhythmia Research, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Wang N; Center for Arrhythmia Research, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Blin MG; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Goldstein DR; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.; Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA., Michel Espinoza-Fonseca L; Center for Arrhythmia Research, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2021 Dec 28; Vol. 20, pp. 380-384. Date of Electronic Publication: 2021 Dec 28 (Print Publication: 2022).
DOI:	10.1016/j.csbj.2021.12.031
Abstrakt:	Phospholamban (PLN) and Sarcolipin (SLN) are homologous membrane proteins that belong to the family of proteins that regulate the activity of the cardiac calcium pump (sarcoplasmic reticulum Ca 2+ -ATPase, SERCA). PLN and SLN share highly conserved leucine zipper motifs that control self-association; consequently, it has been proposed that both PLN and SLN assemble into stable pentamers in the membrane. In this study, we used molecular dynamics (MD) simulations and Western blot analysis to investigate the precise molecular architecture of the PLN and SLN oligomers. Analysis showed that the PLN pentamer is the predominant oligomer present in mouse ventricles and ventricle-like human iPSC-derived cardiomyocytes, in agreement with the MD simulations showing stable leucine zipper interactions across all protomer-protomer interfaces and MD replicates. Interestingly, we found that the PLN pentamer populates an asymmetric structure of the transmembrane region, which is likely an intrinsic feature of the oligomer in a lipid bilayer. The SLN pentamer is not favorably formed across MD replicates and species of origin; instead, SLN from human and mouse atria primarily populate coexisting dimeric and trimeric states. In contrast to previous studies, our findings indicate that the SLN pentamer is not the predominant oligomeric state populated in the membrane. We conclude that despite their structural homology, PLN and SLN adopt distinct oligomeric states in the membrane. We propose that the distinct oligomeric states populated by PLN and SLN may contribute to tissue-specific SERCA regulation via differences in protomer-oligomer exchange, oligomer-SERCA dynamics, and noise filtering during β-adrenergic stimulation in the heart. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2021 The Authors.)
Databáze:	MEDLINE
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