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Allosteric role of the citrate synthase homology domain of ATP citrate lyase

Author

Listed:
  • Xuepeng Wei

    (University of Pennsylvania
    University of Pennsylvania
    Guangzhou Medical University)

  • Kollin Schultz

    (University of Pennsylvania)

  • Hannah L. Pepper

    (Temple University
    Temple University)

  • Emily Megill

    (Temple University
    Temple University)

  • Austin Vogt

    (University of Pennsylvania
    University of Pennsylvania)

  • Nathaniel W. Snyder

    (Temple University
    Temple University)

  • Ronen Marmorstein

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis.

Suggested Citation

  • Xuepeng Wei & Kollin Schultz & Hannah L. Pepper & Emily Megill & Austin Vogt & Nathaniel W. Snyder & Ronen Marmorstein, 2023. "Allosteric role of the citrate synthase homology domain of ATP citrate lyase," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37986-9
    DOI: 10.1038/s41467-023-37986-9
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    References listed on IDEAS

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    1. Jia Wei & Silvana Leit & Jun Kuai & Eric Therrien & Salma Rafi & H. James Harwood & Byron DeLaBarre & Liang Tong, 2019. "An allosteric mechanism for potent inhibition of human ATP-citrate lyase," Nature, Nature, vol. 568(7753), pages 566-570, April.
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