Extracellular cap domain is an essential component of the TRPV1 gating mechanism

Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in a variety of human diseases. Several structures of the founding member of the TRP channel family, TRPV1, are available, all of which were determined for the protein missing the N- and C-termini and the extracellular S5P-loop. Here, we present structures of the full-length thirteen-lined ground squirrel TRPV1 solved by cryo-EM. Our structures resolve the extracellular cap domain formed by the S5-P-loops and the C-terminus that wraps around the three-stranded β-sheet connecting elements of the TRPV1 intracellular skirt. The cap domain forms a dome above the pore’s extracellular entrance, with four portals leading to the ion conductance pathway. Deletion of the cap increases the TRPV1 average conductance, reduces the open probability and affects ion selectivity. Our data show that both the termini and the cap domain are critical determinants of TRPV1 function.

Fig. 1 Structure of full-length sqTRPV1. a–c Side (a), top (b) and bottom (c) views of full-length sqTRPV1 structure with four subunits coloured differently, the cap domain in blue and the C-terminus in pink. Dark blue sphere is a putative chloride ion. d Close-up view of the C-terminus with the residues contributing to interactions with other domains shown in sticks. Asparagine N126, the serine substitution of which converts weakly temperature-sensitive sqTRPV1 into highly temperature-sensitive rTRPV1-like channel, is labelled. See journal link.

This work was done in collaboration with Dr. Sviatoslav N. Bagriantsev & Dr. Elena O. Gracheva groups from Yale University.

See also Columbia University Press release about this work here