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

doi:10.1038/ncomms3722

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 journal › Article › peer-review

81 Scopus citations

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 language	English (US)
Article number	2722
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3722
State	Published - 2013
Externally published	Yes

ASJC Scopus subject areas

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

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10.1038/ncomms3722

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@article{3854de83806e409f8eae2af490b00b30,

title = "Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase",

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-{\AA} 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.",

author = "Chunfeng Zhu and Wenying Gao and Ke Zhao and Xiaohong Qin and Yinjie Zhang and Xin Peng and Lei Zhang and Yuhui Dong and Wenyan Zhang and Peng Li and Wei Wei and Yong Gong and Yu, {Xiao Fang}",

note = "Funding Information: We thank Drs Tao Jiang, Ying Zhang, Wenwen Zheng, Xiaoxia Yu and Mei Li for technical assistance; Drs Haig H. Kazazian, Jr., John L. Goodier and J. Boeke for critical reagents; Sean Prigge, Wei Xie, Wei Qi and Xiaohong Zhou for thoughtful discussions; and Deborah McClellan for editorial assistance. We also thank the staff and management of the Photo Factory (Japan) beamline 17A and Shanghai Synchrotron Radiation Facility beamline 17U for assistance with data collection. This work was supported in part by funding from the Chinese Ministry of Science and Technology (number 2012CB911100 and number 2013ZX0001-005) and Chinese Ministry of Education (number IRT1016), the Key Laboratory of Molecular Virology, Jilin Province (20102209), China, and funding from Tianjin University.",

year = "2013",

doi = "10.1038/ncomms3722",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

AU - Zhu, Chunfeng

AU - Gao, Wenying

AU - Zhao, Ke

AU - Qin, Xiaohong

AU - Zhang, Yinjie

AU - Peng, Xin

AU - Zhang, Lei

AU - Dong, Yuhui

AU - Zhang, Wenyan

AU - Li, Peng

AU - Wei, Wei

AU - Gong, Yong

AU - Yu, Xiao Fang

N1 - Funding Information: We thank Drs Tao Jiang, Ying Zhang, Wenwen Zheng, Xiaoxia Yu and Mei Li for technical assistance; Drs Haig H. Kazazian, Jr., John L. Goodier and J. Boeke for critical reagents; Sean Prigge, Wei Xie, Wei Qi and Xiaohong Zhou for thoughtful discussions; and Deborah McClellan for editorial assistance. We also thank the staff and management of the Photo Factory (Japan) beamline 17A and Shanghai Synchrotron Radiation Facility beamline 17U for assistance with data collection. This work was supported in part by funding from the Chinese Ministry of Science and Technology (number 2012CB911100 and number 2013ZX0001-005) and Chinese Ministry of Education (number IRT1016), the Key Laboratory of Molecular Virology, Jilin Province (20102209), China, and funding from Tianjin University.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms3722

DO - 10.1038/ncomms3722

M3 - Article

C2 - 24217394

AN - SCOPUS:84887670233

SN - 2041-1723

VL - 4

JO - Nature communications

JF - Nature communications

M1 - 2722

ER -

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

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