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Structural basis of the P4B ATPase lipid flippase activity

Author

Listed:
  • Lin Bai

    (Peking University)

  • Bhawik K. Jain

    (Vanderbilt University)

  • Qinglong You

    (Van Andel Institute)

  • H. Diessel Duan

    (Van Andel Institute)

  • Mehmet Takar

    (Vanderbilt University)

  • Todd R. Graham

    (Vanderbilt University)

  • Huilin Li

    (Van Andel Institute)

Abstract

P4 ATPases are lipid flippases that are phylogenetically grouped into P4A, P4B and P4C clades. The P4A ATPases are heterodimers composed of a catalytic α-subunit and accessory β-subunit, and the structures of several heterodimeric flippases have been reported. The S. cerevisiae Neo1 and its orthologs represent the P4B ATPases, which function as monomeric flippases without a β-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the structure of a P4B ATPase, Neo1, in its E1-ATP, E2P-transition, and E2P states. The structure reveals a conserved architecture as well as highly similar functional intermediate states relative to dimeric flippases. Consistently, structure-guided mutagenesis of residues in the proposed substrate translocation path disrupted Neo1’s ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26273-0
    DOI: 10.1038/s41467-021-26273-0
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    References listed on IDEAS

    as
    1. 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.
    2. Ian J. McGough & Reinoud E. A. Groot & Adam P. Jellett & Marco C. Betist & Katherine C. Varandas & Chris M. Danson & Kate J. Heesom & Hendrik C. Korswagen & Peter J. Cullen, 2018. "SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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