Figure 8: Crucial role of the N-terminal domain in the gating of MscL.

(a) The N-terminal domain interacts tightly with the lipid bilayer. It orients at the lipid–solvent interface on the cytoplasmic side and acts as an anchor in stabilizing the closed state of the channel. As the lipid bilayer is stretched, the N-terminal helix is stretched following the trajectory of its surrounding lipid molecules but never becomes completely buried. Then, force is transmitted via the Gly14 residue to the end of TM1, which causes the alignment of TM1 with the N-terminal domain and the formation of a contiguous helix. If we extend the Gly linker (+5 G), we observe that one of the main roles of the N terminus is in expanding the pore. These functions are largely diminished in the +5G model because of the fact that TM1 does not follow the trajectory of the N-terminal region. (b,c) Horizontal membrane-coupling helices seem to be a hallmark of mechanosensitive channels. These helices maybe buried as in the N terminus of MscL, TM3b of MscS and the S4–S5 linker of TRPV4 or adsorbed on the membrane surface as in the C terminus of TREK channels. Owing to the various types of lipids present in different organisms and the divergent ways in which these coupling helices can interact, there is little to no necessity for sequence conservation despite the fact that they play an almost identical role.