Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

Qingfeng Chen, Ji She, Weizhong Zeng, Jiangtao Guo, Haoxing Xu, Xiao Chen Bai, Youxing Jiang

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 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 Ca2+-blocking site that confers luminal pH and Ca2+ 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.

Original languageEnglish (US)
Article number24035
JournalNature
Volume550
Issue number7676
DOIs
StatePublished - Oct 19 2017

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Phosphatidylinositol 4,5-Diphosphate
Mucolipidoses
Ions
Lysosomal Storage Diseases
Cryoelectron Microscopy
Divalent Cations
Static Electricity
Mutagenesis
Cations
Binding Sites
Ligands
Mutation
Membranes
phosphatidylinositol 3,5-diphosphate

ASJC Scopus subject areas

  • General

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Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. / Chen, Qingfeng; She, Ji; Zeng, Weizhong; Guo, Jiangtao; Xu, Haoxing; Bai, Xiao Chen; Jiang, Youxing.

In: Nature, Vol. 550, No. 7676, 24035, 19.10.2017.

Research output: Contribution to journalArticle

Chen Q, She J, Zeng W, Guo J, Xu H, Bai XC et al. Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature. 2017 Oct 19;550(7676). 24035. https://doi.org/10.1038/nature24035
Chen, Qingfeng ; She, Ji ; Zeng, Weizhong ; Guo, Jiangtao ; Xu, Haoxing ; Bai, Xiao Chen ; Jiang, Youxing. / Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. In: Nature. 2017 ; Vol. 550, No. 7676.
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