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

Charalampos Kapsalis, Bolin Wang, Hassane El Mkami, Samantha J. Pitt, Jason R. Schnell, Terry K. Smith, Jonathan D. Lippiat, Bela E. Bode and Christos Pliotas ()
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Charalampos Kapsalis: University of St Andrews
Bolin Wang: University of St Andrews
Hassane El Mkami: University of St Andrews
Samantha J. Pitt: University of St Andrews
Jason R. Schnell: University of Oxford
Terry K. Smith: University of St Andrews
Jonathan D. Lippiat: University of Leeds
Bela E. Bode: University of St Andrews
Christos Pliotas: University of St Andrews

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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 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.

Date: 2019
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DOI: 10.1038/s41467-019-12591-x

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