The structure of lipid nanodisc-reconstituted TRPV3 reveals the gating mechanism
The structure of lipid nanodisc-reconstituted TRPV3 reveals the gating mechanism
复制标题
DOI：
10.1038/s41594-020-0439-z
复制
发表时间：
2020-06-22
影响因子：
16.8
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Shimada, Hiroto;Kusakizako, Tsukasa;Nureki, Osamu
瞬时受体电位香草酸亚家族成员3（TRPV 3）是温度敏感性阳离子通道。先前对TRPV 3在洗涤剂胶束或两性分子中的冷冻-EM分析提出，下门通过附近S6螺旋的α-至-π螺旋转变打开。然而，目前尚不清楚生理脂质如何参与TRPV 3激活。在这里，我们以3.3埃的分辨率确定了脂质纳米盘中小鼠（小家鼠）TRPV 3的载脂蛋白状态结构。结构显示，结合到孔域的脂质使选择性过滤器稳定在窄状态，表明TRPV 3的选择性过滤器影响阳离子渗透。当在纳米盘重构的TRPV 3中关闭下门时，S6螺旋采用π螺旋构象，而没有激动剂或热敏化，可能通过推定的亚基内氢键和脂质结合来稳定。我们的研究结果为TRPV 3的脂质相关门控机制提供了新的见解。小鼠TRPV 3在纳米盘中的冷冻电镜结构显示脂质结合到孔结构域，使选择性过滤器稳定在窄状态，S6稳定在π-螺旋构象。
Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by alpha-to-pi 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 pi-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.A cryo-EM structure of mouse TRPV3 in nanodiscs reveal lipids bound to the pore domain, stabilizing the selectivity filter in the narrow state and the S6 in a pi-helical conformation.