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Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase
- Source :
- Nature communications. 4
- Publication Year :
- 2013
-
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-A 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.
- Subjects :
- Allosteric regulation
Static Electricity
General Physics and Astronomy
Plasma protein binding
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
SAM Domain and HD Domain-Containing Protein 1
Tetramer
Catalytic Domain
Hydrolase
medicine
Humans
heterocyclic compounds
Monomeric GTP-Binding Proteins
Mutation
Multidisciplinary
biology
Chemistry
Hydrolysis
DGTP binding
Active site
Deoxyguanine Nucleotides
General Chemistry
U937 Cells
Recombinant Proteins
HEK293 Cells
Long Interspersed Nucleotide Elements
Biochemistry
biology.protein
HIV-1
Protein Multimerization
Ultracentrifugation
Allosteric Site
SAMHD1
Protein Binding
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....e3ec9c2f9e41cc5ce025b520309b0937