TRPV6 is a highly calcium-selective TRP channel that is responsible for calcium uptake in epithelial cells. Genetic knockout of TRPV6 or the closely related TRPV5 in mice results in phenotypes related to deficits in calcium homeostasis. Links between TRPV6 expression and the proliferation of various cancers has generated interest in TRPV6 as a potential target for cancer diagnostics or therapeutics. We recently solved the crystal structure of TRPV6, which represents the first reported crystal structure of any TRP channel. From the structure (Fig. 1), we obtained the first view of its overall architecture and gleaned new insights into its calcium selective permeation. Using crystallographic techniques, we identified various sites for the binding of calcium and other cations in the TRPV6 pore, allowing us to speculate on a structural mechanism of calcium selective permeation. We are currently interested in further exploring the gating and permeation mechanisms of TRPV6 and other TRP channels.
Figure 1. TRPV6 crystal structure. A) Overall view of the TRPV6 tetramer, with the transmembrane domain, conserved TRP helix, and intracellular skirt colored differently. B) close-up view of the TRPV6 pore, with back and front subunits removed for clarity. Solvent accessible surface is shown in green and various components of the pore are labeled. The pore’s outer vestibule contains acidic residues that may attract cations. The narrow constriction formed by the aspartate ring at the upper entrance determines the unique calcium selectivity of TRPV6. Toward the midpoint of the membrane, the pore widens into a hydrophobic cavity. The lower gate is defined by methionine side chains that plug the permeation pathway. C) Crystallographically identified cation binding sites. Cations (green spheres) bind at recruitment sites at the outer vestibule and three sites along the central pore axis.
Read the paper in Nature.