NDLI: Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel

Content Provider	PubMed Central
Author	Brohawn, Stephen G. Campbell, Ernest B. Mackinnon, Roderick
Abstract	Activation of mechanosensitive ion channels by physical force underlies many physiological processes including the sensation of touch, hearing and pain 1–5 . TRAAK ion channels are neuronally expressed members of the two-pore domain K+ (K2P) channel family and are mechanosensitive 6 . They are involved in controlling mechanical and temperature nociception in mice 7 . Mechanosensitivity of TRAAK is mediated directly through the lipid bilayer: it is a membrane tension gated channel 8 . However, the molecular mechanism of TRAAK channel gating and mechanosensitivity is unknown. Here we present crystal structures of TRAAK in conductive and nonconductive conformations defined by the presence of permeant ions along the conduction pathway. In the nonconductive state, a lipid acyl chain accesses the channel cavity through a 5 Å-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of a transmembrane helix (TM4) about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures reveals a biophysical explanation for TRAAK mechanosensitivity: an expansion in cross sectional area up to 2.7 nm2 in the conductive state is expected to create a membrane tension-dependent energy difference between conformations that promotes force activation. Our results show how tension of the lipid bilayer can be harnessed to control gating and mechanosensitivity of a eukaryotic ion channel.
Related Links	http://dx.doi.org/10.1038/nature14013
Ending Page	130
Page Count	5
Starting Page	126
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7529
Volume Number	516
Language	English
Publisher Date	2014-12-01
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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