Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 3, Pages 205-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3362
Keywords
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Funding
- National Key Basic Research Program of China [2014CB910301]
- National Institutes of Health [R01GM085234, RO1NS053494]
- National Natural Science Foundation of China [31370821, 31570730]
- Top Talents Program of Yunnan Province [2011HA012]
- High-level Overseas Talents of Yunnan Province
- China Youth 1000-Talent Program of the State Council of China
- Beijing Advanced Innovation Center for Structural Biology
- Tsinghua-Peking Joint Center for Life Sciences
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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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