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Allosteric Activation of SAMHD1 by Deoxynucleotidetriphosphate (dNTP)-Dependent Tetramerization Requires dNTP Concentrations That Are Similar to dNTP Concentrations Observed in Cycling T Cells.

Allosteric Activation of SAMHD1 by Deoxynucleotidetriphosphate (dNTP)-Dependent Tetramerization Requires dNTP Concentrations That Are Similar to dNTP Concentrations Observed in Cycling T Cells.
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Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F, Ivanov DN,


Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F, Ivanov DN, (click to view)

Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F, Ivanov DN,

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The Journal of biological chemistry 2016 8 26() pii

Abstract

SAMHD1 is a deoxynucleotidetriphosphate (dNTP) hydrolase, whose activity is required for maintaining low dNTP concentrations in non-cycling T cells, dendritic cells and macrophages. SAMHD1-dependent dNTP depletion is thought to impair retroviral replication in these cells, but the relationship between the dNTPase activity and retroviral restriction is not fully understood. In this study we investigate allosteric activation of SAMHD1 by deoxynucleotide-dependent tetramerization, and measure how the lifetime of the enzymatically active tetramer is affected by different dNTP ligands bound in the allosteric site. The EC50 (dNTP) values for SAMHD1 activation by dNTPs are in the 2-20 μM range, and the half-life of the assembled tetramer after deoxynucleotide depletion varies from minutes to hours depending on what dNTP is bound in the A2 allosteric site. Comparison of the wild-type SAMHD1 and the T592D mutant reveals that the phosphomimetic mutation affects the rates of tetramer dissociation, but has no effect on the equilibrium of allosteric activation by deoxynucleotides. Collectively, our data suggest that deoxynucleotide-dependent tetramerization contributes to regulation of deoxynucleotide levels in cycling cells, whereas in non-cycling cells restrictive to retroviral replication SAMHD1 activation is likely to be achieved through a distinct mechanism.

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