Structural basis of dual Ca 2+ /pH regulation of the endolysosomal TRPML1 channel
文献类型：期刊论文
| 作者 | Li MH1; Zhang WK2,3; Li H2,5; Wang S2,5; Michailidis IE1; Tong L1; Li XM4; Yang J[*]1,2; Benvin NM1; Zhou XY4 |
| 刊名 | NATURE STRUCTURAL & MOLECULAR BIOLOGY
 |
| 出版日期 | 2016 |
| 卷号 | **期号:**页码:published online |
| 通讯作者 | jy160@columbia.edu |
| 英文摘要 | The activities of organellar ion channels are often regulated by Ca2+ and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca2+/pH regulation of TRPML1, a Ca2+-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architecture occurs in the full-length channel. Structure–function studies demonstrated that Ca2+and H+ interact with the luminal pore and exert physiologically important regulation. The MLIV-causing mutations disrupt the luminal-domain structure and cause TRPML1 mislocalization. Our study reveals the structural underpinnings of TRPML1's regulation, assembly and pathogenesis. |
| 收录类别 | SCI |
| 资助信息 | This work was supported by grants to J.Y. from the National Key Basic Research Program of China (2014CB910301), the National Institutes of Health (R01GM085234 and RO1NS053494), the National Natural Science Foundation of China (31370821), the Top Talents Program of Yunnan Province (2011HA012) and the High-level Overseas Talents of Yunnan Province; and grants to X.L. from the China Youth 1000-Talent Program of the State Council of China, the Beijing Advanced Innovation Center for Structural Biology, the Tsinghua-Peking Joint Center for Life Sciences and the National Natural Science Foundation of China (31570730). |
| 语种 | 英语 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10840]  |
| 专题 | 昆明动物研究所_离子通道药物研发中心 昆明动物研究所_动物模型与人类重大疾病机理重点实验室 昆明动物研究所_化学生物学中心 |
| 作者单位 | 1.Department of Biological Sciences, Columbia University, New York, New York, USA 2.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province; and Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China 3.Department of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China 4.Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China 5.Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China. |
| 推荐引用方式 GB/T 7714 | Li MH,Zhang WK,Li H,et al. Structural basis of dual Ca 2+ /pH regulation of the endolysosomal TRPML1 channel[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY,2016,**(**):published online. |
| APA | Li MH.,Zhang WK.,Li H.,Wang S.,Michailidis IE.,...&Su DY.(2016).Structural basis of dual Ca 2+ /pH regulation of the endolysosomal TRPML1 channel.NATURE STRUCTURAL & MOLECULAR BIOLOGY,**(**),published online. |
| MLA | Li MH,et al."Structural basis of dual Ca 2+ /pH regulation of the endolysosomal TRPML1 channel".NATURE STRUCTURAL & MOLECULAR BIOLOGY **.**(2016):published online. |
入库方式： OAI收割
来源：昆明动物研究所
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