Molecular basis of force-from-lipids gating in the mechanosensitive channel MscS

Abstract
Data availability
Article and author information
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Abstract

Prokaryotic mechanosensitive (MS) channels open by sensing the physical state of the membrane. As such, lipid-protein interactions represent the defining molecular process underlying mechanotransduction. Here, we describe cryo-electron microscopy (cryo-EM) structures of the E. coli small-conductance mechanosensitive channel (MscS) in nanodiscs (ND). They reveal a novel membrane-anchoring fold that plays a significant role in channel activation and establish a new location for the lipid bilayer, shifted ~14 Å from previous consensus placements. Two types of lipid densities are explicitly observed. A phospholipid that 'hooks' the top of each TM2-TM3 hairpin and likely plays a role in force sensing, and a bundle of acyl chains occluding the permeation path above the L105 cuff. These observations reshape our understanding of force-from-lipids gating in MscS and highlight the key role of allosteric interactions between TM segments and phospholipids bound to key dynamic components of the channel.

Data availability

EM maps and atomic models have been deposited at the Electron Microscopy Data Bank (accession numbers EMD-20508, EMD-20510, EMD-20509, and EMD-20148) and the Protein Data Back (entry codes 6PWN, 6PWP and 6PWO).

The following data sets were generated

1. Reddy BG
2. Perozo E
(2019) MscS Nanodisc with N-terminal His-Tag
Protein Data Bank, 6PWN.

https://www.rcsb.org/structure/6PWN
1. Reddy BG
2. Perozo E
(2019) MscS Nanodisc
Protein Data Bank, 6PWP.

https://www.rcsb.org/structure/6PWP
1. Reddy BG
2. Perozo E
(2019) MscS DDM
Protein Data Bank, 6PWO.

https://www.rcsb.org/structure/6PWO
1. Reddy BG
2. Perozo E
(2019) MscS Nanodisc with N-terminal His-Tag
Electron Microscopy Data Bank, EMD-20508.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20508
1. Reddy BG
2. Perozo E
(2019) MscS Nanodisc
Electron Microscopy Data Bank, EMD-20510.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20510
1. Reddy BG
2. Perozo E
(2019) MscS DDM
Electron Microscopy Data Bank, EMD-20509.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-20509

Article and author information

Author details

Bharat Reddy

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Navid Bavi

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Allen Lu

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Yeonwoo Park

Department of Ecology and Evolution, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Eduardo Perozo

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States

For correspondence
eperozo@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7132-2793

Funding

National Institute of General Medical Sciences (R01GM131191)

Eduardo Perozo

National Institute of General Medical Sciences (U54GM087519)

Eduardo Perozo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.