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An open-pore structure of the mechanosensitive channel MscL derived by determining transmembrane domain interactions upon gating

^* Department of Physiology, University of Texas, Southwestern Medical Center at Dallas, Dallas Texas, USA

¹ Correspondence: Department of Physiology, University of Texas, Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA. E-mail: paul.blount{at}utsouthwestern.edu

Mechanosensation, the ability to detect mechanical forces, underlies the senses of hearing, balance, touch, and pain, as well as renal and cardiovascular regulation. Although the sensors are thought to be channels, relatively little is known about eukaryotic mechanosensitive channels or their molecular mechanisms. Thus, because of its tractable nature, a bacterial mechanosensitive channel that serves as an in vivo osmotic "emergency release valve," MscL, has become a paradigm of how a mechanosensitive channel can sense and respond to membrane tension. Here, we have determined the structural rearrangements and interactions between transmembrane domains of MscL that occur upon gating. We utilize an electrostatic repulsion test: If two residues approach upon gating we predicted that substituting like-charges at those sites would inhibit gating. The in vivo growth and viability and in vitro vesicular flux and electrophysiological data all support the hypothesis that residues G26 and I92 directly interact upon gating. The resulting model predicted other interacting residues. One of these sets, V23 and I96, was confirmed to truly interact upon gating by disulfide trapping as well as the electrostatic repulsion test. Together, the data strongly suggest a model for structural transitions and residue-residue proximities that occur upon MscL gating.—Li, Y., Wray, R., Eaton, C., Blount, P. An open-pore structure of the mechanosensitive channel MscL derived by determining transmembrane domain interactions upon gating.

Key Words: electrostatic repulsion • mechanosensation • MTS reagents • disulfide trapping • osmotic regulation