Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis

Oliver J. Acton, Devon Sheppard, Simone Kunzelmann, Sarah J. Caswell, Andrea Nans, Ailidh J. O. Burgess, Geoff Kelly, Elizabeth R. Morris, Peter B. Rosenthal () and Ian A. Taylor ()
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Oliver J. Acton: The Francis Crick Institute
Devon Sheppard: The Francis Crick Institute
Simone Kunzelmann: The Francis Crick Institute
Sarah J. Caswell: The Francis Crick Institute
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
Peter B. Rosenthal: The Francis Crick Institute
Ian A. Taylor: The Francis Crick Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48237-w

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