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Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

Author

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  • Chunfeng Zhu

    (School of Life Sciences, Tianjin University)

  • Wenying Gao

    (Institute of Virology and AIDS Research, First Hospital of Jilin University)

  • Ke Zhao

    (Institute of Virology and AIDS Research, First Hospital of Jilin University)

  • Xiaohong Qin

    (School of Life Sciences, Tianjin University)

  • Yinjie Zhang

    (School of Life Sciences, Nankai University)

  • Xin Peng

    (School of Life Sciences, Tianjin University)

  • Lei Zhang

    (School of Life Sciences, Tianjin University)

  • Yuhui Dong

    (Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences)

  • Wenyan Zhang

    (Institute of Virology and AIDS Research, First Hospital of Jilin University)

  • Peng Li

    (Institute of Virology and AIDS Research, First Hospital of Jilin University)

  • Wei Wei

    (Institute of Virology and AIDS Research, First Hospital of Jilin University
    Johns Hopkins Bloomberg School of Public Health)

  • Yong Gong

    (Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences)

  • Xiao-Fang Yu

    (School of Life Sciences, Tianjin University
    Institute of Virology and AIDS Research, First Hospital of Jilin University
    Johns Hopkins Bloomberg School of Public Health)

Abstract

SAMHD1 is a dGTP-activated deoxynucleoside triphosphate triphosphohydrolase (dNTPase) whose dNTPase activity has been linked to HIV/SIV restriction. The mechanism of its dGTP-activated dNTPase function remains unclear. Recent data also indicate that SAMHD1 regulates retrotransposition of LINE-1 elements. Here we report the 1.8-Å crystal structure of homotetrameric SAMHD1 in complex with the allosteric activator and substrate dGTP/dATP. The structure indicates the mechanism of dGTP-dependent tetramer formation, which requires the cooperation of three subunits and two dGTP/dATP molecules at each allosteric site. Allosteric dGTP binding induces conformational changes at the active site, allowing a more stable interaction with the substrate and explaining the dGTP-induced SAMHD1 dNTPase activity. Mutations of dGTP binding residues in the allosteric site affect tetramer formation, dNTPase activity and HIV-1 restriction. dGTP-triggered tetramer formation is also important for SAMHD1-mediated LINE-1 regulation. The structural and functional information provided here should facilitate future investigation of SAMHD1 function, including dNTPase activity, LINE-1 modulation and HIV-1 restriction.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3722
    DOI: 10.1038/ncomms3722
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    Cited by:

    1. 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.

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