Abstract
Protein-lipid interactions are a key element of the function of many integral membrane proteins. These potential interactions should be considered alongside the complexity and diversity of membrane lipid composition. Inward rectifier potassium channel (Kir) Kir2.2 has multiple interactions with plasma membrane lipids: Phosphatidylinositol (4, 5)-bisphosphate (PIP2) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP2; and cholesterol inhibits the channel. Molecular dynamics simulations are used to characterize in molecular detail the protein-lipid interactions of Kir2.2 in a model of the complex plasma membrane. Kir2.2 has been simulated with multiple, functionally important lipid species. From our simulations we show that PIP2 interacts most tightly at the crystallographic interaction sites, outcompeting other lipid species at this site. Phosphatidylserine (PS) interacts at the previously identified secondary anionic lipid interaction site, in a PIP2 concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP2 is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein-lipid interactions.
| Original language | English |
|---|---|
| Journal | Proceedings of the National Academy of Sciences (PNAS) |
| Volume | 117 |
| Issue | 14 |
| Pages (from-to) | 7803-7813 |
| Number of pages | 11 |
| ISSN | 0027-8424 |
| DOIs | |
| Publication status | Published - 7 Apr 2020 |
| Externally published | Yes |
Keywords
- Kir channel
- Lipids
- Molecular dynamics
- PIP2
- PS
- Anions/metabolism
- Membrane Proteins/genetics
- Cell Membrane/genetics
- Potassium/metabolism
- Molecular Dynamics Simulation
- Potassium Channels, Inwardly Rectifying/genetics
- Animals
- Lipid Metabolism/genetics
- Lipids/genetics
- Phosphatidylinositol 4,5-Diphosphate/metabolism