Allosteric activation of SAMHD1 protein by deoxynucleotide triphosphate (dNTP)-dependent tetramerization requires dNTP concentrations that are similar to dNTP concentrations observed in cycling T cells

Zhonghua Wang, Akash Bhattacharya, Jessica Villacorta, Felipe Diaz-Griffero, Dmitri N. Ivanov

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

SAMHD1 is a 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. The50dNTP 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 deoxynucleotidedependent 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.

Original languageEnglish (US)
Pages (from-to)21407-21413
Number of pages7
JournalJournal of Biological Chemistry
Volume291
Issue number41
DOIs
StatePublished - Oct 7 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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