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Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis

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journal contribution
posted on 2024-05-07, 11:15 authored by Oliver J Acton, Devon Sheppard, Simone Kunzelmann, Sarah J Caswell, Andrea Nans, Ailidh JO Burgess, Geoff Kelly, Elizabeth R Morris, Peter B Rosenthal, Ian A Taylor
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.


Crick (Grant ID: CC1078, Grant title: Frenkiel CC1078) Crick (Grant ID: CC2106, Grant title: Rosenthal CC2106) Crick (Grant ID: CC2029, Grant title: Taylor CC2029) Crick (Grant ID: CC1068, Grant title: STP Structural Biology)


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