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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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    1. Corey H. Yu & Akash Bhattacharya & Mirjana Persaud & Alexander B. Taylor & Zhonghua Wang & Angel Bulnes-Ramos & Joella Xu & Anastasia Selyutina & Alicia Martinez-Lopez & Kristin Cano & Borries Demeler, 2021. "Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. David Schwefel & Harriet C. T. Groom & Virginie C. Boucherit & Evangelos Christodoulou & Philip A. Walker & Jonathan P. Stoye & Kate N. Bishop & Ian A. Taylor, 2014. "Structural basis of lentiviral subversion of a cellular protein degradation pathway," Nature, Nature, vol. 505(7482), pages 234-238, January.
    3. Flavie Coquel & Maria-Joao Silva & Hervé Técher & Karina Zadorozhny & Sushma Sharma & Jadwiga Nieminuszczy & Clément Mettling & Elodie Dardillac & Antoine Barthe & Anne-Lyne Schmitz & Alexy Promonet &, 2018. "SAMHD1 acts at stalled replication forks to prevent interferon induction," Nature, Nature, vol. 557(7703), pages 57-61, May.
    4. Chunfeng Zhu & Wenying Gao & Ke Zhao & Xiaohong Qin & Yinjie Zhang & Xin Peng & Lei Zhang & Yuhui Dong & Wenyan Zhang & Peng Li & Wei Wei & Yong Gong & Xiao-Fang Yu, 2013. "Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase," Nature Communications, Nature, vol. 4(1), pages 1-9, December.
    5. David C. Goldstone & Valerie Ennis-Adeniran & Joseph J. Hedden & Harriet C. T. Groom & Gillian I. Rice & Evangelos Christodoulou & Philip A. Walker & Geoff Kelly & Lesley F. Haire & Melvyn W. Yap & Lu, 2011. "HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase," Nature, Nature, vol. 480(7377), pages 379-382, December.
    6. Thomas Oellerich & Constanze Schneider & Dominique Thomas & Kirsten M. Knecht & Olga Buzovetsky & Lars Kaderali & Christoph Schliemann & Hanibal Bohnenberger & Linus Angenendt & Wolfgang Hartmann & Ev, 2019. "Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. Kasia Hrecka & Caili Hao & Magda Gierszewska & Selene K. Swanson & Malgorzata Kesik-Brodacka & Smita Srivastava & Laurence Florens & Michael P. Washburn & Jacek Skowronski, 2011. "Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein," Nature, Nature, vol. 474(7353), pages 658-661, June.
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