title: How the TRPA1 receptor transmits painful stimuli: Inner workings revealed by electron cryomicroscopy.
abstract: A new high-resolution structure of a pain-sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP-domain helix similar to TRPV1, a novel ligand-binding site, and an unusual C-terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP-domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically-gated channels. Similarly, the TRPA1 antagonist-binding site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane-proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.
authors.affiliation: Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
authors.forename: Monique S J
authors.initials: MS
authors.lastname: Brewster
authors.affiliation: Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Gaudet
mesh_terms: D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010146:Pain / Q000503:physiopathology*; D010833:Phytic Acid / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D010833:Phytic Acid
keywords: TRP domain; allosteric gating; ankyrin repeats; coiled coil; electron cryomicroscopy; polyphosphates; transient receptor potential ion channels