Speaker
Description
Lipid flippases (P4-ATPases) mediate active transport of phospholipids from the exoplasmic leaflet to the cytoplasmic one, in order to establish and maintain phospholipid asymmetry in eukaryotic membranes. This asymmetry is tightly regulated, and important for numerous cellular processes such as membrane trafficking, signaling, apoptosis, cytokinesis and cell fusion. The human genome encodes 14 different P4-ATPases, a subset of which are linked to severe diseases including cognitive disorders e.g. Alzheimer’s and Parkinson’s disease, diabetes, cancer or liver disorders. For example, mutations of the human lipid flippase ATP8B1, are responsible for inherited intrahepatic cholestasis, a rare liver disease and KO of Atp8b1 in beta cells inhibits glucose-stimulated insulin release. Little is known about the exact involvement of ATP8B1 in these diseases, mainly because of the lack of consensus regarding its transported substrate and on how its activity is regulated. Previously, we have demonstrated that ATP8B1 is autoinhibited by an evolutionary conserved mechanism involving its N- and C-terminal tails and that the activity is tightly regulated by phosphoinositides [1].
Here, we present our most recent results on the structural and functional characterization of the ATP8B1/CDC50A transport cycle. Our single-particle cryo-EM analysis led to 9 different structures revealing the structural changes happening upon ATP binding, autophosphorylation, relief of the autoinhibition, substrate binding and substrate occlusion. Interestingly, our functional data suggest that ATP8B1 has a much broader substrate specificity than initially anticipated and that surprisingly the substrate specificity is not only driven by the lipid head group.
[1] Dieudonné et al. (2020). Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. eLife 11:e75272
| Session | Structural biology |
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