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| Title | Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. |
|---|---|
| Journal, issue, pages | Nature, Vol. 550, Issue 7676, Page 415-418, Year 2017 |
| Publish date | Oct 19, 2017 |
 Authors | Qingfeng Chen / Ji She / Weizhong Zeng / Jiangtao Guo / Haoxing Xu / Xiao-Chen Bai / Youxing Jiang /  |
| PubMed Abstract | Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are ...Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P) binds to the N terminus of the channel-distal from the pore-and the helix-turn-helix extension between segments S2 and S3 probably couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion-binding sites, and the conserved acidic residues form the luminal Ca-blocking site that confers luminal pH and Ca modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing several luminal ion passages to the pore and creating a negative electrostatic trap, with a preference for divalent cations, at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, suggesting an S4-S5 linker-mediated PtdInsP gating mechanism among TRPML channels. |
 External links | Nature / PubMed:29019981 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.59 - 3.75 Å |
| Structure data | EMDB-8881, PDB-5wpq: |
| Chemicals |  ChemComp-NA: |
| Source |
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 Keywords |  MEMBRANE PROTEIN / Ion channel |
