6E7P

cryo-EM structure of human TRPML1 with PI35P2

Summary for 6E7P

• Entry DOI: 10.2210/pdb6e7p/pdb
• EMDB information: 9000
• Descriptor: Mucolipin-1, (1R,2S,3S,4R,5S,6R)-5-{[(R)-[(2R)-2,3-bis{[(1S)-1-hydroxyoctyl]oxy}propoxy](hydroxy)phosphoryl]oxy}-2,4,6-trihydroxycyclohexane-1,3-diyl bis[dihydrogen (phosphate)] (2 entities in total)
• Functional Keywords: human trpml1, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 263342.38

Authors

Schmiege, P.,Li, X. (deposition date: 2018-07-27, release date: 2018-11-28, Last modification date: 2024-11-06)

Primary citation

Fine, M.,Schmiege, P.,Li, X.
Structural basis for PtdInsP2-mediated human TRPML1 regulation.
Nat Commun, 9:4192-4192, 2018

PubMed Abstract: Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P, PtdIns(4,5)P, or ML-SA1 and PtdIns(3,5)P, revealing a unique lipid-binding site. PtdIns(3,5)P and PtdIns(4,5)P bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P induces Y355 to form a π-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.

PubMed: 30305615
DOI: 10.1038/s41467-018-06493-7

Experimental method

ELECTRON MICROSCOPY (3.5 Å)