Allosteric substrate activation of SAMHD1 shapes deoxynucleotide triphosphate imbalances 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 that depends on dNTP binding at allosteric sites and the concomitant tetramerization of the enzyme. The study reveals that SAMHD1 activation involves an inactive tetrameric intermediate with partial occupancy of the allosteric sites. The equilibrium between the inactive and active tetrameric states, which is coupled to cooperative binding/dissociation of at least two allosteric dNTP ligands, controls the dNTPase activity of the enzyme, which, in addition, depends on the identity of the dNTPs occupying the four allosteric sites of the active tetramer. We show how such allosteric regulation determines deoxynucleotide triphosphate lev

SUBMITTER: McCown C 

PROVIDER: S-EPMC10680743 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature