Extracellular cap domain is an essential component of the TRPV1 gating mechanism.
Extracellular cap domain is an essential component of the TRPV1 gating mechanism.
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DOI：
10.1038/s41467-021-22507-3
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发表时间：
2021-04-12
影响因子：
16.6
通讯作者：
Sobolevsky AI
中科院分区：
文献类型：
--
作者：
Nadezhdin KD;Neuberger A;Nikolaev YA;Murphy LA;Gracheva EO;Bagriantsev SN;Sobolevsky AI
瞬时受体电位（TRP）通道是一种多模态分子传感器，参与多种生理过程，并与多种人类疾病有关。TRP通道家族的创始成员TRPV 1的几种结构是可用的，所有这些结构都是针对缺失N-和C-末端以及细胞外S5-P-环的蛋白质确定的。在这里，我们提出了全长十三线地松鼠TRPV 1的结构解决冷冻EM。我们的结构解析了由S5-P-环和C-末端形成的细胞外帽结构域，所述C-末端包裹TRPV 1细胞内裙部的三链β-折叠连接元件。帽结构域在孔的细胞外入口上方形成圆顶，具有通向离子传导途径的四个门户。帽的删除增加了TRPV 1的平均电导，降低了开放概率，并影响离子选择性。我们的数据表明，这两个终端和帽结构域的TRPV 1功能的关键决定因素。来自十三线地松鼠的全长TRPV 1通道的结构和功能表征揭示了细胞外帽结构域和细胞内C-末端的结构，并表明帽结构域在TRPV 1电导和离子选择性中的作用。
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 S5-P-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. Structural and functional characterization of the full-length TRPV1 channel from the thirteen-lined ground squirrel reveal the architecture of the extracellular cap domain and the intracellular C-terminus, and suggest a role of the cap domain in TRPV1 conductance and ion selectivity.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16.6
作者：
Huynh KW;Cohen MR;Jiang J;Samanta A;Lodowski DT;Zhou ZH;Moiseenkova-Bell VY
通讯作者：
Moiseenkova-Bell VY
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Gracheva, Elena O.;Cordero-Morales, Julio F.;Gonzalez-Carcacia, Jose A.;Ingolia, Nicholas T.;Manno, Carlo;Aranguren, Carla I.;Weissman, Jonathan S.;Julius, David
通讯作者：
Julius, David
影响因子：
16.8
作者：
Dosey, Timothy L.;Wang, Zhao;Wensel, Theodore G.
通讯作者：
Wensel, Theodore G.