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-Structure paper
Title | Structural basis of dual Ca/pH regulation of the endolysosomal TRPML1 channel. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 24, Issue 3, Page 205-213, Year 2017 |
Publish date | Jan 23, 2017 |
Authors | Minghui Li / Wei K Zhang / Nicole M Benvin / Xiaoyuan Zhou / Deyuan Su / Huan Li / Shu Wang / Ioannis E Michailidis / Liang Tong / Xueming Li / Jian Yang / |
PubMed 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 ...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 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 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. |
External links | Nat Struct Mol Biol / PubMed:28112729 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.3 - 8.12 Å |
Structure data | EMDB-6669: EMDB-6670: PDB-5tja: PDB-5tjb: PDB-5tjc: |
Chemicals | ChemComp-HOH: |
Source |
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Keywords | TRANSPORT PROTEIN / endolysosomal lumen / tetramer / calcium and pH regulation |