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Cryo-EM structure of the human P4-type flippase ATP8B1-CDC50A in the auto-inhibited E2Pi-PS state
Structural highlights
DiseaseAT8B1_HUMAN Intrahepatic cholestasis of pregnancy;Benign recurrent intrahepatic cholestasis type 1;Progressive familial intrahepatic cholestasis type 1. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry. FunctionAT8B1_HUMAN Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane (PubMed:17948906, PubMed:25315773). May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane (By similarity). Thus may have a role in the regulation of bile acids transport into the canaliculus, uptake of bile acids from intestinal contents into intestinal mucosa or both and protect hepatocytes from bile salts (By similarity). Involved in the microvillus formation in polarized epithelial cells; the function seems to be independent from its flippase activity (PubMed:20512993). Participates in correct apical membrane localization of CDC42, CFTR and SLC10A2 (PubMed:25239307, PubMed:27301931). Enables CDC42 clustering at the apical membrane during enterocyte polarization through the interaction between CDC42 polybasic region and negatively charged membrane lipids provided by ATP8B1 (By similarity). Together with TMEM30A is involved in uptake of the synthetic drug alkylphospholipid perifosine (PubMed:20510206). Required for the preservation of cochlear hair cells in the inner ear (By similarity). May act as cardiolipin transporter during inflammatory injury (By similarity).[UniProtKB:Q148W0][1] [2] [3] [4] [5] Publication Abstract from PubMedSignificanceATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell membrane and eventually, cell death. Thus, defects in ATP8B1 are usually associated with severe human diseases, such as intrahepatic cholestasis. The present structures of ATP8B1 complexed with its auxiliary noncatalytic partners CDC50A and CDC50B reveal an autoinhibited state of ATP8B1 that could be released upon substrate binding. Moreover, release of this autoinhibition could be facilitated by the bile acids, which are key factors that alter the membrane asymmetry of hepatocytes. This enabled us to figure out a feedback loop of bile acids and lipids across the cell membrane. Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding.,Cheng MT, Chen Y, Chen ZP, Liu X, Zhang Z, Chen Y, Hou WT, Zhou CZ Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2118656119. doi: , 10.1073/pnas.2118656119. Epub 2022 Mar 29. PMID:35349344[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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