Recent studies hypothesized that phospholipids stabilize two voltage-sensing arginine residues of certain voltage-gated potassium channels in activated conformations. It remains unclear how lipids directly affect these channels. Here, by examining the conformations of the KvAP in different lipids, we showed that without voltage change, the voltage-sensor domains switched from the activated to the resting state when their surrounding lipids were changed from phospholipids to nonphospholipids. Such lipid-determined conformational change was coupled to the ion-conducting pore, suggesting that parallel to voltage gating, the channel is gated by its annular lipids. Our measurements recognized that the energetic cost of lipid-dependent gating approaches that of voltage gating, but kinetically it appears much slower. Our data support that a channel and its surrounding lipids together constitute a functional unit, and natural nonphospholipids such as cholesterol should exert strong effects on voltage-gated channels. Our first observation of lipid-dependent gating may have general implications to other membrane proteins.
channels, inner membrane proteins of bacteria, open and close in response to mechanical stimuli such as changes in membrane tension during osmotic stress. In bacteria, these channels act as safety valves preventing cell lysis upon hypo-osmotic cell swelling: the channels open under membrane tension to release osmolytes along with water. The MS channels of small conductance, MscS, consist of a large cytoplasmic domain (CD) that features a balloon-like, water filled chamber opening to the cytoplasm through seven side pores and a very narrow distal pore. The CD is apparently a molecular sieve, which minimizes loss of osmolytes and metabolytes during osmoadaptation. Here we use diffusion theory and molecular dynamics simulations to explore the transport kinetics of Glu-and Kþ as representative osmolytes. We suggest that MscS through the openings of its CD acts as a filter that balances passage of Glu-and Kþ, and possibly other osmolytes, to yield a largely neutral efflux and, thereby, reduce cell depolarization in its open state.
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