6E7Y

cryo-EM structure of human TRPML1 with PI45P2

Summary for 6E7Y

• Entry DOI: 10.2210/pdb6e7y/pdb
• EMDB information: 9001
• Descriptor: Mucolipin-1, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate (2 entities in total)
• Functional Keywords: human trpml1, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 263326.25

Authors

Schmiege, P.,Li, X. (deposition date: 2018-07-27, release date: 2018-11-28, Last modification date: 2024-10-30)

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 (3.57 Å)