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TitleAutoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders.
Journal, issue, pagesElife, Vol. 11, Year 2022
Publish dateApr 13, 2022
AuthorsThibaud Dieudonné / Sara Abad Herrera / Michelle Juknaviciute Laursen / Maylis Lejeune / Charlott Stock / Kahina Slimani / Christine Jaxel / Joseph A Lyons / Cédric Montigny / Thomas Günther Pomorski / Poul Nissen / Guillaume Lenoir /
PubMed AbstractP4-ATPases flip lipids from the exoplasmic to the cytosolic leaflet, thus maintaining lipid asymmetry in eukaryotic cell membranes. Mutations in several human P4-ATPase genes are associated with ...P4-ATPases flip lipids from the exoplasmic to the cytosolic leaflet, thus maintaining lipid asymmetry in eukaryotic cell membranes. Mutations in several human P4-ATPase genes are associated with severe diseases, for example in causing progressive familial intrahepatic cholestasis, a rare inherited disorder progressing toward liver failure. ATP8B1 forms a binary complex with CDC50A and displays a broad specificity to glycerophospholipids, but regulatory mechanisms are unknown. Here, we report functional studies and the cryo-EM structure of the human lipid flippase ATP8B1-CDC50A at 3.1 Å resolution. We find that ATP8B1 is autoinhibited by its N- and C-terminal tails, which form extensive interactions with the catalytic sites and flexible domain interfaces. Consistently, ATP hydrolysis is unleashed by truncation of the C-terminus, but also requires phosphoinositides, most markedly phosphatidylinositol-3,4,5-phosphate (PI(3,4,5)P), and removal of both N- and C-termini results in full activation. Restored inhibition of ATP8B1 truncation constructs with a synthetic peptide mimicking the C-terminal segment further suggests molecular communication between N- and C-termini in the autoinhibition and demonstrates that the regulatory mechanism can be interfered with by exogenous compounds. A recurring (G/A)(Y/F)AFS motif of the C-terminal segment suggests that this mechanism is employed widely across P4-ATPase lipid flippases in plasma membrane and endomembranes.
External linksElife / PubMed:35416773 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

13711

7py4

EMDB-13711, PDB-7py4:
Cryo-EM structure of ATP8B1-CDC50A in E2P autoinhibited state
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-BEF:
BERYLLIUM TRIFLUORIDE ION

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / lipid transporter autoinhibition P-type ATPase P4-ATPase CDC50A

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