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

• Published in: Computational and structural biotechnology journal Vol. 20; pp. 380 - 384
• Main Authors: Liu, Andy Y., Aguayo-Ortiz, Rodrigo, Guerrero-Serna, Guadalupe, Wang, Nulang, Blin, Muriel G., Goldstein, Daniel R., Michel Espinoza-Fonseca, L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2022; Research Network of Computational and Structural Biotechnology; Elsevier
• Subjects: Calcium pump; Cardiac calcium regulation; Communications; Membrane proteins; Oligomerization; Phospholamban; Sarcolipin; Sarcolipin; PLN; Oligomerization; SLN; MD; iPSC; POPC; Calcium pump; Phospholamban; SERCA; Cardiac calcium regulation; Membrane proteins; MD, molecular dynamics; iPSC, induced pluripotent stem cells; PLN, phospholamban; SERCA, sarcoplasmic reticulum Ca2+-ATPase; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; SLN, sarcolipin
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2021.12.031

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 Ca2+-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 stablepentamers 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 anintrinsicfeature 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.