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Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets

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Date
10/10/2019
Author
Kapsalis, Charalampos
Wang, Bolin
El Mkami, Hassane
Pitt, Samantha Jane
Schnell, Jason
Smith, Terry K.
Lippiat, Jonathan
Bode, Bela E.
Pliotas, Christos
Funder
BBSRC
The Wellcome Trust
The Leverhulme Trust
Grant ID
BB/R013780/1
099149/Z/12/Z
RPG-2018-397
Keywords
QD Chemistry
QH301 Biology
DAS
BDC
R2C
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Abstract
Lipid availability within transmembrane nano-pockets of ion channels is linked with mechanosensation. However, the effect of hindering lipid-chain penetration into nano-pockets on channel structure has not been demonstrated. Here we identify nano-pockets on the large conductance mechanosensitive channel MscL, the high-pressure threshold channel. We restrict lipid-chain access to the nano-pockets by mutagenesis and sulfhydryl modification, and monitor channel conformation by PELDOR/DEER. For a single site located at the entrance of the nano-pockets and distal to the channel pore we generate an allosteric response in the absence of tension. Single-channel recordings reveal a decrease in the pressure activation threshold of the modified channel and a sub-conducting state in the absence of applied tension. Threshold is restored to wild-type levels upon reduction of the sulfhydryl modification. The modification associated with the conformational change restricts lipid access to the nano-pocket, and interrupts the contact between the membrane and the channel that mediates mechanosensitivity.
Citation
Kapsalis , C , Wang , B , El Mkami , H , Pitt , S J , Schnell , J , Smith , T K , Lippiat , J , Bode , B E & Pliotas , C 2019 , ' Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets ' , Nature Communications , vol. 10 , 4619 . https://doi.org/10.1038/s41467-019-12591-x
Publication
Nature Communications
Status
Peer reviewed
DOI
https://doi.org/10.1038/s41467-019-12591-x
ISSN
2041-1723
Type
Journal article
Rights
Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Description
C.P. is supported by the Royal Society of Edinburgh. C.P. acknowledges support by Tenovus (T15/41) and Carnegie Trust (OS000256) and the University of St Andrews, the University of Leeds and the Chinese Scholarship Council for the C.K. and B.W. studentships respectively. S.J.P. is supported by the Royal Society of Edinburgh. J.S. acknowledges funding from the MRC (M019152 and L018578). B.E.B. and C.P. acknowledge support by the Leverhulme Trust (RPG-2018-397). This work was supported by Wellcome Trust [099149/Z/12/Z] and BBSRC equipment grants (BB/R013780/1).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/18643

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