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Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Structural basis of dual Ca 2+ /pH regulation of the endolysosomal TRPML1 channel.
Nature Structural & Molecular Biology 2017 March
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.
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