Mechanosensation How Do We Feel

What is the molecular basis by which we sense touch? Mechanosensitive (MS) ion channels present an elegant

Figure 1 Structure of integral membrane proteins involved in signal transduction. (A) KcsA potassium ion channel structure [2]; (B) chloride CLC ion channel [3]; (C) mechanosensitive ion channel of large conductance (MscL [1]); (D) MsbA multidrug ABC transporter homolog [1], (E) bacteriorhodopsin [6]; and (F) bovine rhodopsin [5]. The a-helices and P-sheets are colored in red and yellow, respectively. The membrane-spanning portion of the molecule is indicated with green lines.

Figure 1 Structure of integral membrane proteins involved in signal transduction. (A) KcsA potassium ion channel structure [2]; (B) chloride CLC ion channel [3]; (C) mechanosensitive ion channel of large conductance (MscL [1]); (D) MsbA multidrug ABC transporter homolog [1], (E) bacteriorhodopsin [6]; and (F) bovine rhodopsin [5]. The a-helices and P-sheets are colored in red and yellow, respectively. The membrane-spanning portion of the molecule is indicated with green lines.

solution to the need for a rapid signaling response to external physical stimuli. MS channels are classified by their ability to alter their opening probability in response to lateral tension in the lipid bilayer. In bacteria, mechanosensitive ion channels help microbes react to hypoosmotic stress by allowing them to expel cytoplasmic solutes such as ions and small molecules into the surrounding medium. The crystal structure of the mechanosensitive ion channel from Mycobacterium tuberculosis (TB-MscL) gives some clues as to the structural basis of the cellular response to lateral tension in the lipid bilayer resulting from increased osmotic pressure [1]. TB-MscL is arranged as a homopentamer of 15-kDa subunits. The membrane-spanning domain of the channel consists of ten transmembrane a-helices that are significantly tilted relative to the normal of the cell membrane. The cytoplasmic domain consists of a helix bundle and is likely to be disrupted upon channel opening. MS channels of the MscL family have large conductances on the order of approximately 2.5 nS [8].

Upon channel opening, MscL is thought to form a large pore through the cell membrane with a opening of at least 10 A.

Some unique features of the TB-MscL structure suggest a general mechanism for channel gating in response to lateral tension in the bilayer. First, the gate or "plug" of TB-MscL is located on the inner membrane leaflet side of the cell membrane. Second, there is a cluster of bulky hydrophobic residues positioned to interact directly with neighboring lipid molecules of the inner membrane leaflet. And, finally, the experimentally determined electron density maps have revealed highly ordered lipid/detergent near these bulky residues, suggesting a strong interaction with lipids of the inner membrane leaflet. These features of TB-MscL suggest that structural changes due to lateral tension could be directly transmitted to the transmembrane a-helices via bound lipid. Rearrangement of the transmembrane a-helices causes the plug to pull apart, allowing ion conduction and enabling bacteria to respond rapidly to changing tonicity.

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