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PMID: 21908607 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Molecular architecture and subunit organization of TRPA1 ion channel revealed by electron microscopy.

The Journal of biological chemistry ·Vol. 286 ·No. 44 ·2011-11-04 ·Pages 38168-38176

Cvetkov TL, Huynh KW, Cohen MR, Moiseenkova-Bell VY

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective ion channel, which is expressed in nociceptor sensory neurons and transduces chemical, inflammatory, and neuropathic pain signals. Numerous non-reactive compounds and electrophilic compounds, such as endogenous inflammatory mediators and exogenous pungent chemicals, can activate TRPA1. Here we report a 16-Å resolution structure of purified, functional, amphipol-stabilized TRPA1 analyzed by single-particle EM. Molecular models of the N and C termini of the channel were generated using the I-TASSER protein structure prediction server and docked into the EM density to provide insight into the TRPA1 subunit organization. This structural analysis suggests a location for critical N-terminal cysteine residues involved in electrophilic activation at the interface between neighboring subunits. Our results indicate that covalent modifications within this pocket may alter interactions between subunits and promote conformational changes that lead to channel activation.

MeSH Terms
Animals Calcium/chemistry Chromatography, Gel Circular Dichroism Inflammation Ligands Mice Microscopy, Electron/methods Models, Molecular Molecular Conformation Protein Conformation Protein Structure, Tertiary Saccharomyces cerevisiae/metabolism Structure-Activity Relationship TRPA1 Cation Channel Transient Receptor Potential Channels/metabolism,ultrastructure
Chemicals
Ligands TRPA1 Cation Channel Transient Receptor Potential Channels Trpa1 protein, mouse Calcium
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cvetkov Teresa L
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Huynh Kevin W
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Cohen Matthew R
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Moiseenkova-Bell Vera Y
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: vxm102@case.edu.
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M111.288993
Email
vxm102@case.edu
Published
2011-11-04
Epub
2011-00-09
Pages
38168-38176
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3207480
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M111.288993 PMC Full Text View journal details
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