Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding

Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2118656119. doi: 10.1073/pnas.2118656119. Epub 2022 Mar 29.


SignificanceATP8B1 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.

Keywords: ATP8B1; P4 ATPase; bile acid; cryo-EM structure; phospholipid flippase.

MeSH terms

  • Adenosine Triphosphatases* / metabolism
  • Bile Acids and Salts / metabolism
  • Cell Membrane / metabolism
  • Cholestasis, Intrahepatic* / metabolism
  • Humans
  • Phospholipid Transfer Proteins / metabolism
  • Phospholipids / metabolism


  • Bile Acids and Salts
  • Phospholipid Transfer Proteins
  • Phospholipids
  • Adenosine Triphosphatases
  • ATP8B1 protein, human