Fig. 10: Models of R919*-conferred channel hyperactivity.

a R919* TRPA1 patients are heterozygotes and carry WT and R919* TRPA1 copies. WT and R919* hTRPA1 protein subunits can assemble into separate homomeric complexes that are active and inactive, respectively. WT and R919* hTRPA1 subunits may also co-assemble into hyperactive hetero-tetrameric channels of four possible subunit stoichiometries and configurations. We propose these heteromeric channels confer gain-of-function. b In WT TRPA1 channels, electrophile agonist-evoked gating involves rearrangements in the cytoplasmic domains including conformational flipping of the activation loop, contraction of the coiled coil and adjacent ankyrin repeat domain (ARD), and a sliding rotation of the TRP domain towards the central channel axis (light green arrows). These conformational changes occur with concerted dilation of the upper and lower gates in the S6 transmembrane helix and selectivity filter, which are coupled through straightening of the S5 transmembrane helix (dark green arrows). Loss of the cytoplasmic C-terminus and S6 transmembrane helix in the R919* mutant contribute to conferred hyperactivity in WT-R919* heteromer channels to different degrees (indicated by gradations of pink). Electrophile modification (orange star) of reactive cysteines (yellow circle) in R919* subunits may communicate channel activation to the pore through associated WT subunits via contraction of the ARD and coiled coil domains (purple arrow 1) that could propagate up to the allosteric nexus (purple arrow 2). Two subunits are shown for clarity.