In prokaryotes, MscL and MscS are the foundational members of two structurally distinct classes of MS channels ( Cox et al., 2018 Kung et al., 2010 Naismith and Booth, 2012). Nevertheless, understanding the nature of the lipid forces that drive MS channel gating continues to be one of the fundamental questions in biological mechanotransduction. To explain this phenomenon, several physical properties of the lipid bilayer have been considered ( Perozo, 2006). When the membrane is stretched, the resulting change in the trans-bilayer pressure profile will drive the conformational equilibrium of membrane proteins ( Cantor, 1999 Gullingsrud and Schulten, 2004). Many of these functions are driven by the activity of mechanosensitive channels, switches that couple force sensing with the electrical activity of cells ( Cox et al., 2018 Naismith and Booth, 2012 Perozo, 2006 Sukharev and Corey, 2004). Remarkably, some have evolved as force transducers, where they participate in a variety of fundamental biological functions, including turgor control in plants, development and morphogenesis, touch, hearing, proprioception, as well as osmoregulation in bacteria ( Haswell et al., 2011 Katta et al., 2015 Kung, 2005 Ladoux and Mège, 2017 Murthy et al., 2017). In principle, all molecules are mechanosensitive. 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. 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. Two types of lipid densities are explicitly observed. 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. coli small-conductance mechanosensitive channel (MscS) in nanodiscs (ND). Here, we describe cryo-electron microscopy (cryo-EM) structures of the E. As such, lipid-protein interactions represent the defining molecular process underlying mechanotransduction. Prokaryotic mechanosensitive (MS) channels open by sensing the physical state of the membrane.
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