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Structure paper

TitleStructural basis for PtdInsP-mediated human TRPML1 regulation.
Journal, issue, pagesNat Commun, Vol. 9, Issue 1, Page 4192, Year 2018
Publish dateOct 10, 2018
AuthorsMichael Fine / Philip Schmiege / Xiaochun Li /
PubMed AbstractTransient 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 ...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.
External linksNat Commun / PubMed:30305615 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 3.73 Å
Structure data

9000

6e7p

EMDB-9000, PDB-6e7p:
cryo-EM structure of human TRPML1 with PI35P2
Method: EM (single particle) / Resolution: 3.5 Å

9001

6e7y

EMDB-9001, PDB-6e7y:
cryo-EM structure of human TRPML1 with PI45P2
Method: EM (single particle) / Resolution: 3.57 Å

9002

6e7z

EMDB-9002, PDB-6e7z:
cryo-EM structure of human TRPML1 with ML-SA1 and PI35P2
Method: EM (single particle) / Resolution: 3.73 Å

Chemicals

ChemComp-HZ7:
(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)]

ChemComp-PIO:
[(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

ChemComp-AQV:
2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / human TRPML1

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