Effects of membrane lipids on phospholamban pentameric channel structure and ion transportation mechanisms

Protein-lipid interactions are an essential element of the function of many membrane ion-channel proteins. These potential interactions should be considered alongside the diversity and complexity of membrane lipid compo-sition. Phospholamban (PLN) is an inhibitor of sarcoplasmic reticulum Ca2+ ATPase (SERCA). PLN is a 52-residue transmembrane protein encoded by lncRNA, and PLN monomers form stable pentamers of biological function in a lipid bilayer membrane. Some earlier studies suggest that it can form a cationic selective channel, while others suggest that it can only store ions. Here, we report the distribution of different lipids in the membrane and the structural dynamics and conductance properties of PLN pentamers after coarse-grained (CG) and all-atom (AA) molecular dynamics simulations of different systems. The results show that cholesterol is highly enriched around the protein and stabilizes the structure of the PLN pentamer. The absence of cholesterol increases the flexibility of the protein backbone. The conductance properties of monovalent ions and water suggest that they cannot spontaneously permeate through the PLN pentamer channel pore. However, the energy barrier to overcome is much lower in the absence of cholesterol, underlining the need to fully consider multiple lipid species when investigating small transmembrane protein oligomer ion-channel structure and conductance.

Automated summary

Protein-lipid interactions play a crucial role in the function of membrane ion-channel proteins, which should be considered along with the diversity and complexity of membrane lipid composition. In this study, the distribution of different lipids in the membrane and the structure and conductance properties of phospholamban (PLN) pentamers were investigated through molecular dynamics simulations. The results suggest that cholesterol enriches around the protein, stabilizing the structure of PLN pentamers. The absence of cholesterol increases the flexibility of the protein backbone and lowers the energy barrier for ion permeation.