| First Author | Chen Q | Year | 2017 |
| Journal | Nature | Volume | 550 |
| Issue | 7676 | Pages | 415-418 |
| PubMed ID | 29019981 | Mgi Jnum | J:250436 |
| Mgi Id | MGI:6103412 | Doi | 10.1038/nature24035 |
| Citation | Chen Q, et al. (2017) Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature 550(7676):415-418 |
| abstractText | 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)P2) 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(2+)-blocking site that confers luminal pH and Ca(2+) 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 PtdInsP2 gating mechanism among TRPML channels. |
