Accounting for lipids in protein allostery

The lipid bilayer of biological membranes has been considered an inert medium for embedded proteins. However, recent studies showed that some lipids can affect membrane protein function.

To better understand how certain lipids regulate membrane proteins, Westerlund et al. extended residue interaction networks, a graphing tool for studying proteins, to include lipids and other small molecules such as ligands.

Analysis of the obtained networks and their components revealed the importance of lipids in membrane protein allostery, a mechanism in which the functional site of a protein is affected by changes that happen at a structurally distant site.

Residue interaction networks have been used to study allostery in membrane proteins, but haven’t been used to study lipid bilayers due to their fluid and dynamic nature. The authors overcame the problem by accounting for the lipids’ interchangeability in their networks.

After producing extended networks for three membrane proteins, the authors found that lipids can affect membrane function in different ways. They found the lipids are strongly involved in the allostery of the voltage-gated cardiac ion channel KCNQ1, possibly due to the lipids sometimes getting stuck in the protein’s deep clefts. The networks for a G-protein coupled receptor called β2AR, and a pH-gated ion channel called KcsA, demonstrated how small molecules may allosterically couple and decouple the protein from the membrane.

“This work accounts for lipids, which are increasingly scrutinized when working on membrane protein problems,” said author Lucie Delemotte. “This is maybe particularly important since membrane proteins are abundant drug targets.”

Next, the authors will use the extended framework to study interactions between lipids and membrane proteins that are relevant to medicine.

Source: “Network analysis reveals how lipids and other cofactors influence membrane protein allostery,” by Annie M. Westerlund, Oliver Fleetwood, Sergio Pérez-Conesa, and Lucie Delemotte, Journal of Chemical Physics (2020). The article can be accessed at https://aip.scitation.org/doi/10.1063/5.0020974 . This paper is part of the open 2020 JCP Emerging Investigators Special Collection, learn more here . Submission Deadline: December 31, 2020.