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Structural basis for lipid and copper regulation of the ABC transporter MsbA

Author

Listed:
  • Jixing Lyu

    (Texas A&M University)

  • Chang Liu

    (University of Chicago)

  • Tianqi Zhang

    (Texas A&M University)

  • Samantha Schrecke

    (Texas A&M University)

  • Nicklaus P. Elam

    (Texas A&M University)

  • Charles Packianathan

    (Texas A&M University
    Pilot Bioproduction Facility)

  • Georg K. A. Hochberg

    (University of Marburg
    University of Marburg)

  • David Russell

    (Texas A&M University)

  • Minglei Zhao

    (University of Chicago)

  • Arthur Laganowsky

    (Texas A&M University)

Abstract

A critical step in lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although LPS binding to the inner cavity of MsbA is well established, the selectivity of MsbA-lipid interactions at other site(s) remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15 Å resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL). We report a 3.6 Å-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5’-diphosphate and vanadate, revealing a distinct KDL binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KDL binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis.

Suggested Citation

  • Jixing Lyu & Chang Liu & Tianqi Zhang & Samantha Schrecke & Nicklaus P. Elam & Charles Packianathan & Georg K. A. Hochberg & David Russell & Minglei Zhao & Arthur Laganowsky, 2022. "Structural basis for lipid and copper regulation of the ABC transporter MsbA," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34905-2
    DOI: 10.1038/s41467-022-34905-2
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    References listed on IDEAS

    as
    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. Xiao Cong & Yang Liu & Wen Liu & Xiaowen Liang & Arthur Laganowsky, 2017. "Allosteric modulation of protein-protein interactions by individual lipid binding events," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
    3. Kallol Gupta & Joseph A. C. Donlan & Jonathan T. S. Hopper & Povilas Uzdavinys & Michael Landreh & Weston B. Struwe & David Drew & Andrew J. Baldwin & Phillip J. Stansfeld & Carol V. Robinson, 2017. "The role of interfacial lipids in stabilizing membrane protein oligomers," Nature, Nature, vol. 541(7637), pages 421-424, January.
    4. Yanyan Li & Benjamin J. Orlando & Maofu Liao, 2019. "Structural basis of lipopolysaccharide extraction by the LptB2FGC complex," Nature, Nature, vol. 567(7749), pages 486-490, March.
    5. Arthur Laganowsky & Eamonn Reading & Timothy M. Allison & Martin B. Ulmschneider & Matteo T. Degiacomi & Andrew J. Baldwin & Carol V. Robinson, 2014. "Membrane proteins bind lipids selectively to modulate their structure and function," Nature, Nature, vol. 510(7503), pages 172-175, June.
    6. Hundeep Kaur & Andrea Lakatos-Karoly & Ramona Vogel & Anne Nöll & Robert Tampé & Clemens Glaubitz, 2016. "Coupled ATPase-adenylate kinase activity in ABC transporters," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
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    Cited by:

    1. Tianqi Zhang & Jixing Lyu & Bowei Yang & Sangho D. Yun & Elena Scott & Minglei Zhao & Arthur Laganowsky, 2024. "Native mass spectrometry and structural studies reveal modulation of MsbA–nucleotide interactions by lipids," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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