Structural Mechanism for Gating of Mechanosensitive Channels

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ABSTRACT Structural Mechanism for Gating of Mechanosensitive Channels Mechanical force sensation mediated by mechanosensitive channels underlies an array of fundamental physiological processes, including hearing, touch, proprioception, osmoregulation, and morphogenesis. Dysfunctional force sensation is associated with numerous diseases including deafness, atherosclerosis, chronic pain and cancer. The prokaryotic mechanosensitive channel of small conductance (MscS) protects bacterial cells from rupture under hypoosmotic downshock. A variety of MscS-like channels, found in many organisms including bacteria, fungi, algae, and plants, form an exceptionally diverse superfamily of channels that are crucial for management of osmotic pressure. MscS homologs are absent in animals, and thus targeting MscS channels in pathogenic microorganisms such as bacteria and fungi could lead to new antimicrobial treatment strategies. Current mechanistic understanding, primarily inferred from studies of the prototypical prokaryotic channel, E. Coli MscS, remains limited. Structural, biochemical, and biophysical analyses of complex membrane proteins such as eukaryotic MscS channels and multi-domain prokaryotic MscS homologs have proven challenging owing to major difficulties in producing sufficiently large quantities of biochemically stable protein samples. We have overcome these critical barriers through recent developments in large-scale protein production and structural and functional analyses of a variety of MscS family members with distinct membrane topologies and domain organizations. Our recent structural and functional studies of a eukaryotic channel MSL1 have uncovered a `flattening and expansion' gating mechanism stemming from a non-planar transmembrane domain at the resting state, which is reminiscent of the evolutionarily and architecturally unrelated mammalian mechanosensitive Piezo channels. These results lead to our central hypothesis that `flattening and expansion' in the transmembrane region may be a unifying gating mechanism. With these exciting developments, we are now able to combine structural biology and electrophysiology to address one of the central questions in mechanobiology: how do mechanosensitive channels gate? Specifically, we aim to reveal gating transitions of a diverse set of MscS channels with distinct membrane topologies to further evaluate this potentially universal gating mechanism. Detailed understanding of the mechanisms will provide critical information that will ultimately lead to development of new antimicrobial reagents and new treatment strategies for a broad spectrum of diseases associated with altered mechanical force sensation.