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Publication : Structure of mammalian endolysosomal TRPML1 channel in nanodiscs.

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.
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