Determining the molecular basis of voltage sensitivity in membrane proteins.

Kasimova MA, Lindahl E, Delemotte L

J. Gen. Physiol. 150 (10) 1444-1458 [2018-10-01; online 2018-08-27]

Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.

Fellows programme

Lucie Delemotte

PubMed 30150239

DOI 10.1085/jgp.201812086

Crossref 10.1085/jgp.201812086

pii: jgp.201812086
pmc: PMC6168238
PDB: 2R9R
PDB: 5HVX
PDB: 4NPQ
PDB: 3UKM
PDB: 2ZW3
PDB: 3EMN
PDB: 3J5R
PDB: 6COY
PDB: 3UON
PDB: 3WGU


Publications 7.1.2