SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs.

ABSTRACT: SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism of SAMHD1, which involves dNTP binding at allosteric sites and transient tetramerization. Our findings reveal that tetramerization alone is insufficient to promote dNTP hydrolysis; instead, the activation mechanism requires an inactive tetrameric intermediate with partially occupied allosteric sites. The equilibrium between inactive and active tetrameric states regulates dNTPase activity, driven by the binding and dissociation of additional allosteric dNTP ligands to the preassembled tetramer. Furthermore, catalytic efficiency, but not substrate specificity, is modulated by the identity of the dNTPs occupying the allosteric sites. We show ho

SUBMITTER: McCown C 

PROVIDER: S-EPMC11742054 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature