Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Year: 2019

Type: article

Abstract: Channelrhodopsin-2 (ChR2) is a light-gated ion channel that conducts cations of multiple valencies down the electrochemical gradient. This light-gated property has made ChR2 a popular tool in the field of optogenetics, allowing for the spatial and temporal control of excitable cells with light. A central aspect of protein function is the interaction with the surrounding lipid environment. To further explore these membrane-protein interactions, we demonstrate the role of residual hydrophobic mismatch (RHM) as a mechanistically important component of ChR2 function. We combined computational and functional experiments to understand how RHM between the lipid environment and ChR2 alters the structural and biophysical properties of the channel. Analysis of our results revealed significant RHM at the intracellular/lipid interface of ChR2 from a triad of residues. The resulting energy penalty is substantial and can be lowered via mutagenesis to evaluate the functional effects of this change in lipid-protein interaction energy. The experimental measurement of channel stability, conductance and selectivity resulting from the reduction of the RHM energy penalty showed changes in progressive H+ permeability, kinetics and open-state stability, suggesting how the modulation of ChR2 by the surrounding lipid membrane can play an important biological role and contribute to the design of targeted optogenetic constructs for specific cell types.

Source: Applied Sciences

DOI: 10.3390/app9132674

Authors: Ryan Richards, Sayan Mondal, Harel Weinstein, Robert E. Dempski

Institutions: Worcester Polytechnic Institute, University of Massachusetts Chan Medical School, Schrodinger (United States), Cornell University, Weill Cornell Medicine

Language: English

Topic: Photoreceptor and optogenetics research

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $1,520

Funders: National Science Foundation, U.S. Department of Energy, National Energy Research Scientific Computing Center, National Institutes of Health, Office of Science, Weill Cornell Medical College, National Institute of Mental Health, National Institute on Drug Abuse

OpenAlex ID: W2954793584