Cryo-EM structure of mouse TRPML2 in lipid nanodiscs.
Cryo-EM structure of mouse TRPML2 in lipid nanodiscs.
复制标题
DOI：
10.1016/j.jbc.2021.101487
复制
发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Song X;Li J;Tian M;Zhu H;Hu X;Zhang Y;Cao Y;Ye H;McCormick PJ;Zeng B;Fu Y;Duan J;Zhang J
在哺乳动物中，瞬时受体电位粘磷脂离子通道（TRPML）对阳离子如Ca 2+、Fe 2+、Zn 2+和Na+表现出可变的渗透性，并且可以被内溶酶体系统中的磷酸肌醇PI（3，5）P2激活。TRPML的丧失或功能障碍与溶酶体贮积症、感染性疾病和代谢性疾病有关。TRPML 2最近被鉴定为内溶酶体细胞器中的机械敏感性和低渗敏感性通道，这将其与TRPML 1和TRPML 3区分开来。然而，TRPML 2的分子和门控机制仍然难以捉摸。在这里，我们提出了全长小鼠TRPML 2在脂质纳米盘中的冷冻电镜结构，分辨率为3.14 nm。TRPML 2 homotetramer结构在pH 7.4的载脂蛋白状态揭示了一个无活性的构象和一些独特的功能extratocytosolic/管腔域和电压传感器样域的离子传导途径的影响。这种结构使新的TRPML通道的不同亚组之间的比较与可用的结构，并提供结构的TRPML通道的保守性和多样性的见解。这些比较对于理解TRPMLs在不同pH条件下的各种分子机制具有广泛的意义，包括有和没有结合的激动剂和拮抗剂。
In mammalians, transient receptor potential mucolipin ion channels (TRPMLs) exhibit variable permeability to cations such as Ca2+, Fe2+, Zn2+, and Na+ and can be activated by the phosphoinositide PI(3,5)P2 in the endolysosomal system. Loss or dysfunction of TRPMLs has been implicated in lysosomal storage disorders, infectious diseases, and metabolic diseases. TRPML2 has recently been identified as a mechanosensitive and hypotonicity-sensitive channel in endolysosomal organelles, which distinguishes it from TRPML1 and TRPML3. However, the molecular and gating mechanism of TRPML2 remains elusive. Here, we present the cryo-EM structure of the full-length mouse TRPML2 in lipid nanodiscs at 3.14 Å resolution. The TRPML2 homotetramer structure at pH 7.4 in the apo state reveals an inactive conformation and some unique features of the extracytosolic/luminal domain and voltage sensor-like domain that have implications for the ion-conducting pathway. This structure enables new comparisons between the different subgroups of TRPML channels with available structures and provides structural insights into the conservation and diversity of TRPML channels. These comparisons have broad implications for understanding a variety of molecular mechanisms of TRPMLs in different pH conditions, including with and without bound agonists and antagonists.
登录
查看更多内容
影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
13.6
作者：
Chen CC;Krogsaeter E;Butz ES;Li Y;Puertollano R;Wahl-Schott C;Biel M;Grimm C
通讯作者：
Grimm C
DOI：
10.1073/pnas.0709846104
发表时间：
2007-12-04
影响因子：
11.1
作者：
Grimm, Christian;Cuajungco, Math P.;Heller, Stefan
通讯作者：
Heller, Stefan
DOI：
10.1002/ajmg.1320410310
发表时间：
1991-12-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
CHITAYAT, D;MEUNIER, CM;CARPENTER, S
通讯作者：
CARPENTER, S
内溶酶体 TRPML1 通道 Ca2/pH 双重调节的结构基础。
影响因子：
16.8
作者：
Li M;Zhang WK;Benvin NM;Zhou X;Su D;Li H;Wang S;Michailidis IE;Tong L;Li X;Yang J
通讯作者：
Yang J