Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Poster Abstracts

35-POS Board 9 STATE-DEPENDENT MORPHOLOGICAL DEFORMATIONS OF THE LIPID BILAYER EXPLAIN MECHANOSENSITIVE GATING OF MSCS CHANNEL Yein Park 1 ; Eduardo Perozo 2 ; Jose Faraldo-Gomez 1 ; 1 NIH, Bethesda, MD, USA 2 University of Chicago, Chicago, IL, USA Mechanosensitive ion channels are paradigmatic examples of the interdependence between membrane protein structures and the morphology and physical state of the lipid bilayer. Here, we investigate the molecular basis of this interplay by studying the MscS channel from Escherichia coli as well as one of its eukaryotic homologs, namely MSL1 from Arabidopsis thaliana. First, we use single-particle cryo-EM to determine the structure of a seemingly open state of wild-type MscS in a lipid nanodisc. Unlike existing models of this state, this structure does not result from mutation of the channel or detergent solubilization, but it is induced through a modest degree of membrane thinning. Based on this new structure, and on that of a closed state reported recently, we examine how the morphology of the lipid bilayer is altered upon channel gating, using molecular dynamics simulations. The simulations reveal that closed-state MscS causes drastic deformations in the lipid bilayer, which develop to provide adequate solvation to the features of the protein surface, but clearly reflect a high energy state in terms of membrane shape. Strikingly, these deformations are almost entirely eradicated in the open conformation of the channel. An analogous comparison for open and closed states of MSL1, based on existing experimental structures, corroborates these findings. Taken together, these observations strongly suggest that the gating mechanism of MscS and its homologs is dictated by opposing conformational preferences, namely those of the lipid membrane and of the protein structure, and that this coupling ultimately explains why this class of channels are mechanosensitive. Specifically, we theorize that any condition that increases the energetic cost of the membrane deformations required to stabilize the closed state will shift the gating equilibrium towards the conductive form, as this state perturbs the membrane minimally; possible stimuli with such an effect include membrane tension and membrane thinning.

88