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

Chunfeng Zhu, Wenying Gao, Ke Zhao, Xiaohong Qin, Yinjie Zhang, Xin Peng, Lei Zhang, Yuhui Dong, Wenyan Zhang, Peng Li, Wei Wei, Yong Gong () and Xiao-Fang Yu ()
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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
Yong Gong: Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences
Xiao-Fang Yu: School of Life Sciences, Tianjin University

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3722

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