• DOI:10.1073/pnas.2107095118
• Corpus ID: 236977112

Mechanosensitive channel gating by delipidation

@article{Flegler2021MechanosensitiveCG,
  title={Mechanosensitive channel gating by delipidation},
  author={Vanessa Judith Flegler and Akiko Rasmussen and Karina Borbil and Lea Boten and Hsuan-Ai Chen and Hanna Deinlein and Julia Halang and Kristin Hellmanzik and Jessica L{\"o}ffler and Vanessa Schmidt and Cihan Makbul and Christian Kraft and Rainer Hedrich and Tim Rasmussen and Bettina B{\"o}ttcher},
  journal={Proceedings of the National Academy of Sciences},
  year={2021},
  volume={118}
}

• V. Flegler, A. Rasmussen, +12 authors Bettina Böttcher
• Published 10 August 2021
• Biology
• Proceedings of the National Academy of Sciences

Significance Proteins embedded in membranes experience anisotropic forces from their surroundings. Mechanosensors are activated upon changes in the membrane tension and are the basis of important biological functionalities. However, the molecular mechanisms of mechanosensation are only vaguely understood. Hydrophobic mismatch between protein and membrane, amphiphilic sliding helices, or local membrane bending are examples for different concepts explaining mechanosensation in which one or more of these concepts could be implemented in a particular protein. Here, we show that the mechanosensitive channel of small conductance is gated by the extrusion of lipids from hydrophobic pockets independent of the membrane. A cryoelectron microscopy map at 2.3-Å resolution reveals the so-far-neglected role of aliphatic chains at the periplasmatic side in stabilizing the open state. The mechanosensitive channel of small conductance (MscS) protects bacteria against hypoosmotic shock. It can sense the tension in the surrounding membrane and releases solutes if the pressure in the cell is getting too high. The membrane contacts MscS at sensor paddles, but lipids also leave the membrane and move along grooves between the paddles to reside as far as 15 Å away from the membrane in hydrophobic pockets. One sensing model suggests that a higher tension pulls lipids from the grooves back to the membrane, which triggers gating. However, it is still unclear to what degree this model accounts for sensing and what contribution the direct interaction of the membrane with the channel has. Here, we show that MscS opens when it is sufficiently delipidated by incubation with the detergent dodecyl-β-maltoside or the branched detergent lauryl maltose neopentyl glycol. After addition of detergent-solubilized lipids, it closes again. These results support the model that lipid extrusion causes gating: Lipids are slowly removed from the grooves and pockets by the incubation with detergent, which triggers opening. Addition of lipids in micelles allows lipids to migrate back into the pockets, which closes the channel even in the absence of a membrane. Based on the distribution of the aliphatic chains in the open and closed conformation, we propose that during gating, lipids leave the complex on the cytosolic leaflet at the height of highest lateral tension, while on the periplasmic side, lipids flow into gaps, which open between transmembrane helices.