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论文 |
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| 论文题目: |
Structural Basis of Dual Ca2+/pH Regulation of the Endolysosomal TRPML1 Channel |
| 作者: |
Li M, Zhang WK, Benvin NM, Zhou X, Su D, Li H, Wang S, Michailidis IE, Tong L, Li X, Yang J |
| 联系作者: |
jianyang@mail.kiz.ac.cn |
| 发表年度: |
2017 |
| DOI: |
doi:10.1038/nsmb.3362 |
| 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 forendolysosomal 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 humanTRPML1 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. |
| 刊物名称: |
Nature Structural & Molecular Biology |
| 论文出处: |
http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3362.html |
| 影响因子: |
13.338(2015年) |
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