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ABCA1 is an extracellular phospholipid translocase

Author

Listed:
  • Jere P. Segrest

    (Vanderbilt University Medical Center)

  • Chongren Tang

    (University of Washington)

  • Hyun D. Song

    (Vanderbilt University Medical Center)

  • Martin K. Jones

    (Vanderbilt University Medical Center)

  • W. Sean Davidson

    (University of Cincinnati)

  • Stephen G. Aller

    (University of Alabama at Birmingham)

  • Jay W. Heinecke

    (University of Washington)

Abstract

Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane’s outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1’s outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter’s extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family.

Suggested Citation

  • Jere P. Segrest & Chongren Tang & Hyun D. Song & Martin K. Jones & W. Sean Davidson & Stephen G. Aller & Jay W. Heinecke, 2022. "ABCA1 is an extracellular phospholipid translocase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32437-3
    DOI: 10.1038/s41467-022-32437-3
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    References listed on IDEAS

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    1. Wei Mi & Yanyan Li & Sung Hwan Yoon & Robert K. Ernst & Thomas Walz & Maofu Liao, 2017. "Structural basis of MsbA-mediated lipopolysaccharide transport," Nature, Nature, vol. 549(7671), pages 233-237, September.
    2. Tian Xie & Zike Zhang & Qi Fang & Bowen Du & Xin Gong, 2021. "Structural basis of substrate recognition and translocation by human ABCA4," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Hoangdung Ho & Anh Miu & Mary Kate Alexander & Natalie K. Garcia & Angela Oh & Inna Zilberleyb & Mike Reichelt & Cary D. Austin & Christine Tam & Stephanie Shriver & Huiyong Hu & Sharada S. Labadie & , 2018. "Structural basis for dual-mode inhibition of the ABC transporter MsbA," Nature, Nature, vol. 557(7704), pages 196-201, May.
    4. Jyh-Yeuan Lee & Lisa N. Kinch & Dominika M. Borek & Jin Wang & Junmei Wang & Ina L. Urbatsch & Xiao-Song Xie & Nikolai V. Grishin & Jonathan C. Cohen & Zbyszek Otwinowski & Helen H. Hobbs & Daniel M. , 2016. "Crystal structure of the human sterol transporter ABCG5/ABCG8," Nature, Nature, vol. 533(7604), pages 561-564, May.
    5. Roger J. P. Dawson & Kaspar P. Locher, 2006. "Structure of a bacterial multidrug ABC transporter," Nature, Nature, vol. 443(7108), pages 180-185, September.
    6. Ignacio Faustino & Haleh Abdizadeh & Paulo C. T. Souza & Aike Jeucken & Weronika K. Stanek & Albert Guskov & Dirk J. Slotboom & Siewert J. Marrink, 2020. "Membrane mediated toppling mechanism of the folate energy coupling factor transporter," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
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