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

ABSTRACT: 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.

SUBMITTER: Cheng MT

PROVIDER: S-EPMC9168909 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Cheng Meng-Ting MT Chen Yu Y Chen Zhi-Peng ZP Liu Xin X Zhang Zhiyong Z Chen Yuxing Y Hou Wen-Tao WT Zhou Cong-Zhao CZ

Proceedings of the National Academy of Sciences of the United States of America 20220329 14

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 rele ...[more]

PMID: 35349344

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