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

Journal article

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 spectroscopy. 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 significant 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, interrupting the contact between the membrane and the channel that mediates mechanosensitivity.

Authors: Kapsalis, C; Wang, B; El Mkami, H; Pitt, SJ; Schnell, JR

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Communications
• Volume: 10
• Issue: 1
• Article number: 4619
• Publication date: 2019-10-10
• Acceptance date: 2019-09-17
• DOI: 10.1038/s41467-019-12591-x
• EISSN: 2041-1723
• Pmid: 31601809
• Language: English
• Keywords: FFR