Network analysis reveals how lipids and other cofactors influence membrane protein allostery

• Published in: The Journal of chemical physics 2020-10, Vol.153 (14), p.141103-141103
• Main Authors: Westerlund, Annie M., Fleetwood, Oliver, Pérez-Conesa, Sergio, Delemotte, Lucie
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Camelids, New World; Cell Membrane - chemistry; Cell Membrane - metabolism; Coupling (molecular); Decoupling; Diffusion rate; Escherichia coli - chemistry; Ion channels; KCNQ1 Potassium Channel - chemistry; KCNQ1 Potassium Channel - metabolism; Lipids; Membranes; Mice; Molecular Dynamics Simulation; Network analysis; Phosphatidylglycerols - chemistry; Phosphatidylglycerols - metabolism; Potassium Channels, Voltage-Gated - chemistry; Potassium Channels, Voltage-Gated - metabolism; Proteins; Receptors; Receptors, Adrenergic, beta-2 - chemistry; Receptors, Adrenergic, beta-2 - metabolism; Residues; Streptomyces lividans - chemistry
• ISSN: 0021-9606; 1089-7690; 1089-7690
• DOI: 10.1063/5.0020974

Many membrane proteins are modulated by external stimuli, such as small molecule binding or change in pH, transmembrane voltage, or temperature. This modulation typically occurs at sites that are structurally distant from the functional site. Revealing the communication, known as allostery, between these two sites is key to understanding the mechanistic details of these proteins. Residue interaction networks of isolated proteins are commonly used to this end. Membrane proteins, however, are embedded in a lipid bilayer, which may contribute to allosteric communication. The fast diffusion of lipids hinders direct use of standard residue interaction networks. Here, we present an extension that includes cofactors such as lipids and small molecules in the network. The novel framework is applied to three membrane proteins: a voltage-gated ion channel (KCNQ1), a G-protein coupled receptor (GPCR—β2 adrenergic receptor), and a pH-gated ion channel (KcsA). Through systematic analysis of the obtained networks and their components, we demonstrate the importance of lipids for membrane protein allostery. Finally, we reveal how small molecules may stabilize different protein states by allosterically coupling and decoupling the protein from the membrane.