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, Xiao Fang Yu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2722
JournalNature communications
Volume4
DOIs
StatePublished - Jan 1 2013

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zhu, C., Gao, W., Zhao, K., Qin, X., Zhang, Y., Peng, X., Zhang, L., Dong, Y., Zhang, W., Li, P., Wei, W., Gong, Y., & Yu, X. F. (2013). Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase. Nature communications, 4, [2722]. https://doi.org/10.1038/ncomms3722