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- Title
Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.
- Authors
Acton, Oliver J.; Sheppard, Devon; Kunzelmann, Simone; Caswell, Sarah J.; Nans, Andrea; Burgess, Ailidh J. O.; Kelly, Geoff; Morris, Elizabeth R.; Rosenthal, Peter B.; Taylor, Ian A.
- 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. SAMHD1 is a regulator of dNTP homeostasis and an HIV restriction factor. The authors use time-resolved cryo-EM to visualise dynamic conformational changes that drive the catalytic cycle and allosteric regulation of this multi-subunit enzyme.
- Subjects
QUATERNARY structure; ALLOSTERIC regulation; ENZYME regulation; ENZYME kinetics; CATALYSIS; ORDER-disorder transitions; HOMEOSTASIS
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48237-w