Effects of amino acid modifications on the permeability of the pentameric sarcolipin channel

Abstract

Sarcolipin (SLN) is an important transmembrane (TM) protein encoded by long noncoding RNA. SLN is expressed in the sarcoplasmic reticulum and regulates cardiac and skeletal muscle contractions. SLN forms a pentameric hydrophobic ligand‐gated ion channel. The protonation of Glu7 (protonated SLN, pSLN) and mutation of Thr18 to Ala18 (T18A) have been reported to exert a significant influence on the permeability of the channel. In this study, the altered permeability of both the pSLN and T18A pentameric channels was simulated. Combined with molecular dynamics simulation, the free‐energy landscape for single ions, computational electrophysiology, diffusion coefficient, and pore geometrical characteristic analyses were performed to further understand the properties of amino acid modifications in the SLN pentameric channel. The results suggest that both the pSLN and T18A pentameric channels form stable hydrophobic ligand‐gated channels. The TM voltage has a positive effect on the permeability of water molecules and ions. By using pSLN and T18A, our study provides helpful information on the pore‐forming mechanism of SLN and furthers our understanding of the regulatory mechanisms underlying the permeation of ions and water molecules in the pentameric SLN channel.

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

“…These findings, which are reproducible across replicates, species of origin, and primary antibodies ( Figs. S7-S8 ), are in contrast with previous studies suggesting that pentamers are the primary oligomeric form of SLN in the membrane [12] , [13] , [14] . There is excellent agreement between simulations and experiments demonstrating that the pentamer is the main oligomeric form of PLN, whereas SLN primarily populates coexisting dimeric and trimeric states in the membrane.…”

“…Like the PLN pentamer, the modeled structure of the SLN pentamer is characterized by a cyclic point symmetry with the axis running perpendicular to the membrane plane. We also point out that the SLN pentamer generated in this study is nearly identical to that reported in previous computational studies [12] , [13] , [14] ; accordingly, we used this structure as an initial model to perform five independent 1-µs MD simulations of the SLN pentamer in a lipid bilayer composed of POPC lipids. In addition, we performed four independent 1-µs MD simulations of the PLN pentamer starting from the most representative structures extracted from the NMR ensemble.…”

“…PLN and SLN share similar motifs that control self-association and oligomer stoichiometry [9] , [10] , and previous studies have shown that both PLN and SLN assemble into stable and symmetrical pentamers in the membrane [11] , [12] , [13] , [14] . In apparent contradiction with this view, spectroscopy studies have shown that PLN, but not SLN, self-associate into distinct pentamers [15] , and that SLN dimers and higher-order oligomeric may coexist in a membrane environment [9] .…”

Prediction of LncRNA-encoded small peptides in glioma and oligomer channel functional analysis using in silico approaches

“…For example, Huang et al found that the lncRNA HOXB-AS3 encodes micro peptides that can bind to heterogeneous nuclear ribonucleoproteins (hnRNPs) and suppress glucose metabolism reprogramming in colon cancer [13]. SLN, PLB, MLN, and DWORF [14][15][16] are involved in some physiological processes of diseases by regulating skeletal muscle activity via interaction with sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) [17]. Surprisingly, Ji et al found that more than 40% of lncRNA fragments encode proteins and that more than half of these fragments are in the form of small peptides (median number of amino acids < 46) [18].…”