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Title | Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. |
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Journal, issue, pages | Elife, Vol. 11, Year 2022 |
Publish date | Apr 13, 2022 |
Authors | Thibaud 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 Abstract | 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 ...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 links | Elife / PubMed:35416773 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.1 Å |
Structure data | EMDB-13711, PDB-7py4: |
Chemicals | ChemComp-MG: ChemComp-BEF: ChemComp-Y01: ChemComp-NAG: |
Source |
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Keywords | MEMBRANE PROTEIN / lipid transporter autoinhibition P-type ATPase P4-ATPase CDC50A |