The role of lipids in mechanosensation

Christos Pilotas, A Caroline E Dahl, Tim Rasmussen, Kozhinjampara R Mahendran, Terry K Smith, Phedra Marius, Joseph Gault, Thandiwe Banda, Akiko Rasmussen, Samantha Miller, Carol V Robinson, Hagan Bayley, Mark S P Sansom, Ian Rylance Booth, James H Naismith

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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.
Original languageEnglish
Pages (from-to)991-998
Number of pages8
JournalNature Structural & Molecular Biology
Volume22
Issue number12
Early online date9 Nov 2015
DOIs
Publication statusPublished - Dec 2015

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Phospholipids
Lipids
Escherichia coli
Membranes
Molecular Dynamics Simulation
Fluorescence
Proteins

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Pilotas, C., Dahl, A. C. E., Rasmussen, T., Mahendran, K. R., Smith, T. K., Marius, P., ... Naismith, J. H. (2015). The role of lipids in mechanosensation. Nature Structural & Molecular Biology, 22(12), 991-998. https://doi.org/10.1038/nsmb.3120

The role of lipids in mechanosensation. / Pilotas, Christos; Dahl, A Caroline E; Rasmussen, Tim; Mahendran, Kozhinjampara R; Smith, Terry K; Marius, Phedra; Gault, Joseph ; Banda, Thandiwe; Rasmussen, Akiko; Miller, Samantha; Robinson, Carol V; Bayley, Hagan; Sansom, Mark S P; Booth, Ian Rylance; Naismith, James H.

In: Nature Structural & Molecular Biology, Vol. 22, No. 12, 12.2015, p. 991-998.

Research output: Contribution to journalArticle

Pilotas, C, Dahl, ACE, Rasmussen, T, Mahendran, KR, Smith, TK, Marius, P, Gault, J, Banda, T, Rasmussen, A, Miller, S, Robinson, CV, Bayley, H, Sansom, MSP, Booth, IR & Naismith, JH 2015, 'The role of lipids in mechanosensation', Nature Structural & Molecular Biology, vol. 22, no. 12, pp. 991-998. https://doi.org/10.1038/nsmb.3120
Pilotas C, Dahl ACE, Rasmussen T, Mahendran KR, Smith TK, Marius P et al. The role of lipids in mechanosensation. Nature Structural & Molecular Biology. 2015 Dec;22(12):991-998. https://doi.org/10.1038/nsmb.3120
Pilotas, Christos ; Dahl, A Caroline E ; Rasmussen, Tim ; Mahendran, Kozhinjampara R ; Smith, Terry K ; Marius, Phedra ; Gault, Joseph ; Banda, Thandiwe ; Rasmussen, Akiko ; Miller, Samantha ; Robinson, Carol V ; Bayley, Hagan ; Sansom, Mark S P ; Booth, Ian Rylance ; Naismith, James H. / The role of lipids in mechanosensation. In: Nature Structural & Molecular Biology. 2015 ; Vol. 22, No. 12. pp. 991-998.
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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.",
author = "Christos Pilotas and Dahl, {A Caroline E} and Tim Rasmussen and Mahendran, {Kozhinjampara R} and Smith, {Terry K} and Phedra Marius and Joseph Gault and Thandiwe Banda and Akiko Rasmussen and Samantha Miller and Robinson, {Carol V} and Hagan Bayley and Sansom, {Mark S P} and Booth, {Ian Rylance} and Naismith, {James H}",
note = "Acknowledgements: 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.",
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AU - Marius, Phedra

AU - Gault, Joseph

AU - Banda, Thandiwe

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AU - Miller, Samantha

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AU - Bayley, Hagan

AU - Sansom, Mark S P

AU - Booth, Ian Rylance

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N1 - Acknowledgements: 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.

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N2 - 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.

AB - 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.

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