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Autoinhibition and activation mechanisms of the eukaryotic lipid flippase Drs2p-Cdc50p

Author

Listed:
  • Lin Bai

    (Structural Biology Program, Van Andel Research Institute)

  • Amanda Kovach

    (Structural Biology Program, Van Andel Research Institute)

  • Qinglong You

    (Structural Biology Program, Van Andel Research Institute)

  • Hao-Chi Hsu

    (Structural Biology Program, Van Andel Research Institute)

  • Gongpu Zhao

    (David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute)

  • Huilin Li

    (Structural Biology Program, Van Andel Research Institute)

Abstract

The heterodimeric eukaryotic Drs2p-Cdc50p complex is a lipid flippase that maintains cell membrane asymmetry. The enzyme complex exists in an autoinhibited form in the absence of an activator and is specifically activated by phosphatidylinositol-4-phosphate (PI4P), although the underlying mechanisms have been unclear. Here we report the cryo-EM structures of intact Drs2p-Cdc50p isolated from S. cerevisiae in apo form and in the PI4P-activated form at 2.8 Å and 3.3 Å resolution, respectively. The structures reveal that the Drs2p C-terminus lines a long groove in the cytosolic regulatory region to inhibit the flippase activity. PIP4 binding in a cytosol-proximal membrane region triggers a 90° rotation of a cytosolic helix switch that is located just upstream of the inhibitory C-terminal peptide. The rotation of the helix switch dislodges the C-terminus from the regulatory region, activating the flippase.

Suggested Citation

  • Lin Bai & Amanda Kovach & Qinglong You & Hao-Chi Hsu & Gongpu Zhao & Huilin Li, 2019. "Autoinhibition and activation mechanisms of the eukaryotic lipid flippase Drs2p-Cdc50p," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12191-9
    DOI: 10.1038/s41467-019-12191-9
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    Cited by:

    1. Lin Bai & Bhawik K. Jain & Qinglong You & H. Diessel Duan & Mehmet Takar & Todd R. Graham & Huilin Li, 2021. "Structural basis of the P4B ATPase lipid flippase activity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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