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

Lin Bai (), Amanda Kovach, Qinglong You, Hao-Chi Hsu, Gongpu Zhao and Huilin Li ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12191-9

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