Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase.
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.
1] School of Life Sciences, Tianjin University, Tianjin 300072, China [2].
Chunfeng
C
Zhu
Wenying
W
Gao
Ke
K
Zhao
Xiaohong
X
Qin
Yinjie
Y
Zhang
Xin
X
Peng
Lei
L
Zhang
Yuhui
Y
Dong
Wenyan
W
Zhang
Peng
P
Li
Wei
W
Wei
Yong
Y
Gong
Xiao-Fang
XF
Yu
D000495:Allosteric Site; D020134:Catalytic Domain; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020084:Long Interspersed Nucleotide Elements; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D055672:Static Electricity; D020298:U937 Cells; D014461:Ultracentrifugation
D003848:Deoxyguanine Nucleotides; D011994:Recombinant Proteins; C029603:deoxyguanosine triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins