The role of lipids in mechanosensation
Abstract
The ability of proteins to sense membrane tension is pervasive in biology. A higher-resolution structure of the Escherichia coli small-conductance mechanosensitive channel MscS identifies alkyl chains inside pockets formed by the transmembrane helices (TMs). Purified MscS contains E. coli lipids, and fluorescence quenching demonstrates that phospholipid acyl chains exchange between bilayer and TM pockets. Molecular dynamics and biophysical analyses show that the volume of the pockets and thus the number of lipid acyl chains within them decreases upon channel opening. Phospholipids with one acyl chain per head group (lysolipids) displace normal phospholipids (with two acyl chains) from MscS pockets and trigger channel opening. We propose that the extent of acyl-chain interdigitation in these pockets determines the conformation of MscS. When interdigitation is perturbed by increased membrane tension or by lysolipids, the closed state becomes unstable, and the channel gates.
Additional Information
© 2015 Nature Publishing Group. Received 9 June; accepted 6 October; published online 9 November 2015. This work was supported by Wellcome Trust grants WT092552MA (J.H.N. and I.R.B.), Senior Investigator Award WT100209MA (J.H.N.), 093228 (T.K.S.) and 092970 (M.S.P.S.), and Biotechnology and Biological Sciences Research Council grants BB/I019855/1 (M.S.P.S.), BB/H017917/1 (J.H.N. and I.R.B.) and BB/J009784/1 (H.B.). We acknowledge the Diamond Light Source for beam time. I.R.B. is supported as a Leverhulme Emeritus Fellow. J.H.N. is supported as a Royal Society Wolfson Merit Award holder and as a 1000 Talent Scholar at Sichuan University. A.C.E.D. was supported by an Engineering and Physical Sciences Research Council Systems Biology Doctoral Training Centre student fellowship. We thank R. Phillips, A. Lee and S. Conway for helpful discussions. These authors contributed equally to this work. Christos Pliotas, A Caroline E Dahl, Tim Rasmussen & Kozhinjampara R Mahendran Author Contributions:C.P. purified and spin-labeled MscS for lipid analysis, single-molecule analysis and crystallization; obtained and analyzed the new crystal structure; and participated in the single-molecule and lipid-analysis experiments. T.R. purified MscS and carried out and analyzed the fluorescence studies including synthesis of brominated lipids. A.C.E.D. wrote the MD-analysis software and performed and analyzed the simulations. K.R.M. performed and analyzed single-molecule experiments. A.R. made mutants of MscS and performed osmotic downshock assays. T.B. assisted in fluorescence experiments. T.K.S. performed lipidomic mass spectrometry. C.V.R. and J.G. carried out native mass spectrometry. P.M. performed TLC experiments. S.M., H.B., M.S.P.S., I.R.B. and J.H.N. conceived and supervised the study. All authors wrote, reviewed and approved the paper. The authors declare no competing financial interests.Attached Files
Accepted Version - emss_65544.pdf
Supplemental Material - 41594_2015_BFnsmb3120_MOESM15_ESM.pdf
Supplemental Material - nsmb_3120-SF1.jpg
Supplemental Material - nsmb_3120-SF2.jpg
Supplemental Material - nsmb_3120-SF3.jpg
Supplemental Material - nsmb_3120-SF4.jpg
Supplemental Material - nsmb_3120-SF5.jpg
Supplemental Material - nsmb_3120-SF6.jpg
Supplemental Material - nsmb_3120-sv1.mpeg
Supplemental Material - nsmb_3120-sv2.mpeg
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Additional details
- PMCID
- PMC4675090
- Eprint ID
- 62121
- DOI
- 10.1038/nsmb.3120
- Resolver ID
- CaltechAUTHORS:20151116-104333476
- WT092552MA
- Wellcome Trust
- WT100209MA
- Wellcome Trust
- 093228
- Wellcome Trust
- 092970
- Wellcome Trust
- B/I019855/1
- Biotechnology and Biological Sciences Research Council (BBSRC)
- BB/H017917/1
- Biotechnology and Biological Sciences Research Council (BBSRC)
- BB/J009784/1
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Leverhulme Trust
- Royal Society
- Engineering and Physical Sciences Research Council (EPSRC)
- Created
-
2015-11-17Created from EPrint's datestamp field
- Updated
-
2023-09-27Created from EPrint's last_modified field