Phospholamban and Sarcolipin Share Similar Transmembrane Zipper Motifs That Control Self-Association Affinity and Homo-Oligomer Stoichiometry.
- 1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street S.E., Minneapolis, MN 55455, USA.
Abstract
We characterized the structural determinants of phospholamban (PLB) and sarcolipin (SLN) self-assembly, using experimental and computational assays. PLB and SLN are transmembrane peptides that regulate contractility via phosphorylation-dependent regulation of the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). The physiological role of PLB and SLN has been proposed to be important as a reservoir for fine-tuning SERCA activity and to act as ion-selective channels. Structural studies of PLB and SLN transmembrane domains have indicated stabilization of higher-order oligomers by leucine/isoleucine zippers in a heptad-repeat motif (a-g residue positions), requiring residue C41. Here we have modeled and tested the additional residues responsible for self-assembly using alanine replacement. We demonstrate that PLB e-position residues in the cleft between subunits contribute to self-association affinity and stoichiometry. For SLN, we identified two residues (V14, L21) and a novel heptad repeat (a-position) that contribute to self-association affinity and stoichiometry. This is in addition to the d-position that we previously identified for SLN oligomerization. Our molecular models demonstrate stable hexamer assemblies, but without the likelihood of a hydrated pore. We propose that PLB and SLN populate a distribution of oligomeric forms in sarcoplasmic reticulum membranes (monomer through pentamer and hexamer) and suggest that pore formation requires increased toroidal stoichiometry.
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BibTeX
@article{svensson2026phospholamban,
title = {{Phospholamban and Sarcolipin Share Similar Transmembrane Zipper Motifs That Control Self-Association Affinity and Homo-Oligomer Stoichiometry.}},
author = {Bengt Svensson and Joseph M Autry and John E Rubin and Robyn T Rebbeck and David D Thomas},
journal = {Membranes},
year = {2026},
month = sep,
doi = {10.3390/membranes16100323},
url = {https://europepmc.org/article/MED/42931001},
note = {CC BY},
}
RIS
TY - JOUR
TI - Phospholamban and Sarcolipin Share Similar Transmembrane Zipper Motifs That Control Self-Association Affinity and Homo-Oligomer Stoichiometry.
AU - Bengt Svensson
AU - Joseph M Autry
AU - John E Rubin
AU - Robyn T Rebbeck
AU - David D Thomas
PY - 2026
DA - 2026/09/28
JO - Membranes
DO - 10.3390/membranes16100323
UR - https://europepmc.org/article/MED/42931001
AB - We characterized the structural determinants of phospholamban (PLB) and sarcolipin (SLN) self-assembly, using experimental and computational assays. PLB and SLN are transmembrane peptides that regulate contractility via phosphorylation-dependent regulation of the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). The physiological role of PLB and SLN has been proposed to be important as a reservoir for fine-tuning SERCA activity and to act as ion-selective channels. Structural studies of PLB and SLN transmembrane domains have indicated stabilization of higher-order oligomers by leucine/isoleucine zippers in a heptad-repeat motif (a-g residue positions), requiring residue C41. Here we have modeled and tested the additional residues responsible for self-assembly using alanine replacement. We demonstrate that PLB e-position residues in the cleft between subunits contribute to self-association affinity and stoichiometry. For SLN, we identified two residues (V14, L21) and a novel heptad repeat (a-position) that contribute to self-association affinity and stoichiometry. This is in addition to the d-position that we previously identified for SLN oligomerization. Our molecular models demonstrate stable hexamer assemblies, but without the likelihood of a hydrated pore. We propose that PLB and SLN populate a distribution of oligomeric forms in sarcoplasmic reticulum membranes (monomer through pentamer and hexamer) and suggest that pore formation requires increased toroidal stoichiometry.
SN - 2077-0375
ER -