[YSA] Young Scientist Award Symposium

[YSA-4(2P-18)] The structure of lipid nanodisc-reconstituted TRPV3 reveals the gating mechanism

^○Hiroto Shimada¹, Tsukasa Kusakizako¹, Nguyen T. H. Dung³, Tomohiro Nishizawa¹, Tomoya Hino², Makoto Tominaga³, Osamu Nureki¹ (1.Dept. of Biol. Sci., Grad. Sch. of Sci., Univ. of Tokyo, 2.Dept. of Chem. and Biotech., Grad. Sch. of Eng. Tottori Univ., 3.Div. Cell Signaling, Natl Inst Physiol. Sci.)

Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel, responding to thermal stimuli, while TRPV3 responds to innocuous temperatures or chemical compounds, such as camphor, carvacrol and 2-aminoethoxydiphenyl borate (2-APB), and permeates cations nonselectively. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by α-to-π helical transitions of the nearby S6 helix. However, it remains unclear how physiological lipids are involved in the TRPV3 activation. Here we determined the apo state structure of mouse (Mus musculus) TRPV3 in a lipid nanodisc at 3.3-angstrom resolution. The structure revealed that lipids bound to the pore domain stabilize the selectivity filter in the narrow state, suggesting that the selectivity filter of TRPV3 affects cation permeation. When the lower gate is closed in nanodisc-reconstituted TRPV3, the S6 helix adopts the π-helical conformation without agonist- or heat-sensitization, potentially stabilized by putative intra-subunit hydrogen bonds and lipid binding. Our findings provide insights into the lipid-associated gating mechanism of TRPV3.