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Structural Basis of Dual Ca2+/pH Regulation of the Endolysosomal TRPML1 Channel
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author: |
Li M, Zhang WK, Benvin NM, Zhou X, Su D, Li H, Wang S, Michailidis IE, Tong L, Li X, Yang J |
Abstract: |
The activities of organellar ion channels are often regulated by Ca and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca/pH regulation of TRPML1, a Ca-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 Ca 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
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Page number: |
205-213 |
Issue: |
3 |
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PubYear: |
2017 |
Volume: |
24 |
Unit code: |
152453 |
Publication name: |
Nature Structural & Molecular Biology |
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Paper source: |
https://www.nature.com/nsmb/journal/v24/n3/full/nsmb.3362.html |
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