3.A.1.201.3
Short chain fatty acid phosphatidylcholine translocase (phospholipid flippase), MDR3; AbcB4; Pgy3.  ABCB4 regulates the secretion into bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. It is associated with progressive familial intrahepatic cholestasis type 3 (PFIC3) (Degiorgio et al. 2007) and progressive intrafamilial hepatic disease (Quazi and Molday, 2011)). ABCB4 exhibits narrow drug specificity relative to MDR1 but exports digoxin, paclitaxel, vinblastin and bile acids. It regulates phosphatidylcholine secretion into bile and its translocation across the plasma membrane in hepatocytes (Voloshyna and Reiss, 2011; Kluth et al. 2014) and functions as a floppase (Sakamoto et al. 2019). The cryo-EM structure trapped in an ATP-bound state at a resolution of 3.2 Å has been described (Olsen et al. 2019). The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg²⁺. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound, is present. This indicates a state following substrate release but prior to ATP hydrolysis. These results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters (Olsen et al. 2019). An in vitro assay to investigate ABCB4 transport function has been developed (Temesszentandrási-Ambrus et al. 2023). ABCB4 is located at the canalicular membrane of hepatocytes and is responsible for the secretion of phosphatidylcholine into bile (Lakli et al. 2024). Genetic variations of this transporter are correlated with rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). New small molecular correctors for have been identified to correct traffic-defective ABCB4 variants (Lakli et al. 2024). Progressive familial intrahepatic cholestasis type 3 is caused by ABCB4 gene mutations (Ye et al. 2024).