Structural basis of allosteric activation of Sterile Alpha Motif and Histidine-Aspartate Domain containing protein 1 (SAMHD1) by nucleoside triphosphates [Protein Structure and Folding]

October 6th, 2014 by Koharudin, L. M. I., Wu, Y., DeLucia, M., Mehrens, J., Gronenborn, A. M., Ahn, J.

Sterile alpha motif and Histidine-Aspartate-domain containing protein 1 (SAMHD1) plays a critical role in inhibiting HIV infection, curtailing the pool of dNTPs available for reverse transcription of the viral genome. Recent structural data suggested a compelling mechanism for the regulation of SAMHD1 enzymatic activity, and revealed dGTP-induced association of two inactive dimers into an active tetrameric enzyme. Here, we present the crystal structures of SAMHD1 catalytic core (residues 113-626, SAMHD1c) tetramers, complexed with mixtures of nucleotides, including dGTP/dATP, dGTP/dCTP, dGTP/dTTP, and dGTP/dUTP. The combined structural and biochemical data provide insight into dNTP promiscuity at the secondary allosteric site and how enzymatic activity is modulated. In addition, we present biochemical analyses of GTP-induced SAMHD1 full-length (SAMHD1fl) tetramerization and the structure of SAMHD1c tetramer in complex with GTP/dATP, revealing the structural basis of GTP-mediated SAMHD1 activation. Altogether, the data presented here advance our understanding of SAMHD1 function during cellular homeostasis.
  • Posted in Journal of Biological Chemistry, Publications
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