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Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis

Author

Listed:
  • Oliver J. Acton

    (The Francis Crick Institute
    The Francis Crick Institute
    1 Francis Crick Avenue)

  • Devon Sheppard

    (The Francis Crick Institute)

  • Simone Kunzelmann

    (The Francis Crick Institute)

  • Sarah J. Caswell

    (The Francis Crick Institute
    1 Francis Crick Avenue)

  • Andrea Nans

    (The Francis Crick Institute)

  • Ailidh J. O. Burgess

    (The Francis Crick Institute)

  • Geoff Kelly

    (The Francis Crick Institute)

  • Elizabeth R. Morris

    (The Francis Crick Institute
    University of Durham)

  • Peter B. Rosenthal

    (The Francis Crick Institute)

  • Ian A. Taylor

    (The Francis Crick Institute)

Abstract

SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2’-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.

Suggested Citation

  • Oliver J. Acton & Devon Sheppard & Simone Kunzelmann & Sarah J. Caswell & Andrea Nans & Ailidh J. O. Burgess & Geoff Kelly & Elizabeth R. Morris & Peter B. Rosenthal & Ian A. Taylor, 2024. "Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48237-w
    DOI: 10.1038/s41467-024-48237-w
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