LivFlip · Structural and cellular investigation of the regulation of ATP8B1/CDC50A, a human flippase important for the hepatic function
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-03-01 → 2023-02-28
- EU contribution
- €219,312
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Structural and cellular investigation of the regulation of ATP8B1/CDC50A, a human flippase important for the hepatic function
The inherited intrahepatic hepatic cholestasis is a rare disease characterized by impaired bile flow and a highly toxic accumulation of bile salts in the liver which normally helps digestion and absorption of nutrients in the small intestine. Familial intrahepatic disorders have been linked to five genes implicated in bile salt homeostasis or hepatocyte membrane integrity. Among them, the ATP8B1 gene encodes for a lipid transporter (lipid flippase). However, little is known about the function of ATP8B1 at the canalicular membrane and this is mainly due to the lack of consensus regarding its transport substrate and how its activity is regulated. Thanks to the Marie Curie program, the supported project provided structural and functional information on ATP8B1 autoinhibition, lipid specificity and transport mechanisms.
Data: CORDIS, © European Union
Project objective
Lipid flippases mediate transport of phospholipids from the exoplasmic leaflet to the cytosolic one, and their role is to establish and maintain phospholipid asymmetry in eukaryotic membranes. This asymmetry is tightly regulated and it is implicated in numerous cellular processes such as membrane trafficking, signaling, blood coagulation, apoptosis, cytokinesis, or cell fusion. The human genome encodes 14 different P4-ATPases, a subset of them being linked to pathologies such as mental retardation, Alzheimer’s disease, diabetes, cancer or liver disorders. As concerns the latter disease, it has been demonstrated that mutations of the human lipid flippase ATP8B1, are responsible for inherited intrahepatic cholestasis. The intrahepatic cholestasis affects mostly children and is characterized by pruritus, recurrent jaundice, growth failure and an evolutive liver degradation which requires transplantation before adulthood in most severe cases. Up to now, little is known about the function of ATP8B1 at the canalicular membrane and this is mainly due to the lack of consensus regarding its transport substrate and how its activity is regulated. Preliminary results indicate that ATP8B1 has a broader transport substrate specificity than previously reported in the literature and therefore its study will widen our understanding of the biochemical basis of lipid selectivity in lipid flippases. In addition, in the proposed project I aim at understanding how a disease related lipid flippase, ATP8B1, is regulated in vitro and in vivo and at understanding functional and structural consequences of identified mutations of ATP8B1 linked to the intrahepatic cholestasis.
Original text from CORDIS.
Participants
- AARHUS UNIVERSITET · Aarhus CCoordinatorDenmark
Links
Data: CORDIS, © European Union