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Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis

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

Nature communications, 2024-05, Vol.15 (1), p.3775-3775, Article 3775 [Periódico revisado por pares]

England: Nature Publishing Group

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Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis
Autor: 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
Assuntos: Allosteric properties ; Allosteric Regulation ; Assembly ; Biocatalysis ; Catalysis ; Catalysts ; Catalytic Domain ; CD4 antigen ; Cellular structure ; Cryoelectron Microscopy ; Dynamic structural analysis ; Enzymes ; HIV ; HIV-1 - metabolism ; Homeostasis ; Human immunodeficiency virus ; Humans ; Lymphocytes T ; Macrophages ; Models, Molecular ; Nucleoside analogs ; Nucleotides ; Order-disorder transformations ; Particle analysis ; Protein structure ; Protein Structure, Quaternary ; Quaternary structure ; SAM Domain and HD Domain-Containing Protein 1 - chemistry ; SAM Domain and HD Domain-Containing Protein 1 - genetics ; SAM Domain and HD Domain-Containing Protein 1 - metabolism ; Stabilized platforms
É parte de: Nature communications, 2024-05, Vol.15 (1), p.3775-3775, Article 3775
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SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis

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

England: Nature Publishing Group

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