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

Charalampos Kapsalis, Bolin Wang, Hassane El Mkami, Samantha Jane Pitt, Jason Schnell, Terry K. Smith, Jonathan Lippiat, Bela E. Bode, Christos Pliotas

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)
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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.
Original languageEnglish
Article number4619
Number of pages14
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 10 Oct 2019

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