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 language | English (US) |
|---|---|
| Article number | 24035 |
| Journal | Nature |
| Volume | 550 |
| Issue number | 7676 |
| DOIs | |
| State | Published - Oct 19 2017 |
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Cite this
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 journal › Article
}
TY - JOUR
T1 - Structure of mammalian endolysosomal TRPML1 channel in nanodiscs
AU - Chen, Qingfeng
AU - She, Ji
AU - Zeng, Weizhong
AU - Guo, Jiangtao
AU - Xu, Haoxing
AU - Bai, Xiao Chen
AU - Jiang, Youxing
PY - 2017/10/19
Y1 - 2017/10/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85031944385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031944385&partnerID=8YFLogxK
U2 - 10.1038/nature24035
DO - 10.1038/nature24035
M3 - Article
C2 - 29019981
AN - SCOPUS:85031944385
VL - 550
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7676
M1 - 24035
ER -