Molecular basis of force-from-lipids gating in the mechanosensitive channel MscS

Abstract

Prokaryotic mechanosensitive (MS) channels open by sensing the physical state of the membrane. As such, lipid-protein interactions represent the defining molecular process underlying mechanotransduction. Here, we describe cryo-electron microscopy (cryo-EM) structures of the E. coli small-conductance mechanosensitive channel (MscS) in nanodiscs (ND). They reveal a novel membrane-anchoring fold that plays a significant role in channel activation and establish a new location for the lipid bilayer, shifted ~14 Å from previous consensus placements. Two types of lipid densities are explicitly observed. A phospholipid that ‘hooks’ the top of each TM2-TM3 hairpin and likely plays a role in force sensing, and a bundle of acyl chains occluding the permeation path above the L105 cuff. These observations reshape our understanding of force-from-lipids gating in MscS and highlight the key role of allosteric interactions between TM segments and phospholipids bound to key dynamic components of the channel.

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…Towards the interface region, attracting forces between the carbonyls dominate, generating strong tensions between 1000 and 2000 bar. The head group region of the bilayer is then again usually dominated by intermolecular repulsion between negatively charged phosphate moieties [ 32 , 33 , 34 ]. These interactions give rise to lateral pressure profiles that look for most bilayers comparable to the one depicted in Figure 2 (cf.…”

Structural mechanism for gating of a eukaryotic mechanosensitive channel of small conductance

“…Intrinsically sensitive to membrane tension, MscS channels from several prokaryotes have been extensively characterized and served as a prevailing model system for understanding physicochemical principles in mechanotransduction 9 . X-ray and cryo-electron microscopy (Cryo-EM) structures reveal that each protomer of the homo-heptameric MscS channel consists of three transmembrane helices (TM1-3) followed by a cytoplasmic barrel structure [15][16][17][18][19][20][21][22] . The presumed closed and open structures suggest that TM1 and TM2 constitute a peripheral membrane 'tension sensor', which is attached to the central pore-lining helix TM3a followed by the amphipathic TM3b running approximately parallel to the membrane [15][16][17][18] .…”

“…According to this model, rotation and tilting of TM1 and TM2 as a rigid body under elevated membrane tension, accompanied by displacement of channel-bound lipid molecules, pulls TM3a to open the hydrophobic pore gate 16,18 . However, different gating models derived from electron paramagnetic resonance (EPR) spectroscopy, molecular dynamics (MD) simulations, and recent cryo-EM studies have also been proposed 20,[23][24][25][26] , and these competing models are actively debated 9,20 .…”

Charged pore-lining residues are required for normal channel kinetics in the eukaryotic mechanosensitive ion channel MSL1

“…Multiple structures of EcMscS describe a homoheptameric channel with a transmembrane (TM) domain, comprised of three TM helices per monomer, atop a large cytoplasmic "cage" [17][18][19][20][21][22][23]. A key feature of the EcMscS structure is the porelining TM helix, TM3, which, in the nonconducting state, kinks mid-way through at G113, such that its C-terminal portion points outward from the pore and lies parallel to the lipid bilayer [17,18,20,21]. During gating, TM3 is proposed to pivot outward around and partially straighten this kink, thus removing pore occlusions and allowing for ion flow [18,19,23,24].…”