Title : Structure of mammalian endolysosomal
TRPML1 channel in nanodiscs
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
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 4. channel, terminus
- 5. Ca2, site
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):