5WPQ

Cryo-EM structure of mammalian endolysosomal TRPML1 channel in nanodiscs in closed I conformation at 3.64 Angstrom resolution

Summary for 5WPQ

• Entry DOI: 10.2210/pdb5wpq/pdb
• Related: 5WPO 5WPT 5WPV
• EMDB information: 8881 8882 8883
• Descriptor: Mucolipin-1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, SODIUM ION (3 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 4
• Total formula weight: 268347.84

Authors

Chen, Q.,She, J.,Guo, J.,Bai, X.,Jiang, Y. (deposition date: 2017-08-07, release date: 2017-10-18, Last modification date: 2024-10-23)

Primary citation

Chen, Q.,She, J.,Zeng, W.,Guo, J.,Xu, H.,Bai, X.C.,Jiang, Y.
Structure of mammalian endolysosomal TRPML1 channel in nanodiscs.
Nature, 550:415-418, 2017

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 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.

PubMed: 29019981
DOI: 10.1038/nature24035

Experimental method

ELECTRON MICROSCOPY (3.64 Å)