Open AccessStructural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding
Author(s) -
Meng-Ting Cheng,
Yu Chen,
Zhipeng Chen,
Xin Liu,
Zhiyong Zhang,
Yuxing Chen,
Wentao Hou,
CongZhao Zhou
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2118656119
Subject(s) - flippase , membrane , phospholipid scramblase , microbiology and biotechnology , cell membrane , substrate (aquarium) , chemistry , cell , atpase , biochemistry , biophysics , biology , enzyme , phosphatidylserine , phospholipid , ecology
Significance ATP8B1 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.