Download MendeleyStructural Basis of Allosteric Activation of Sterile alpha Motif and Histidine-Aspartate Domain-containing Protein 1 (SAMHD1) by Nucleoside Triphosphates.
Koharudin, L.M., Wu, Y., DeLucia, M., Mehrens, J., Gronenborn, A.M., Ahn, J.(2014) J Biol Chem 289: 32617-32627
- PubMed: 25288794
- DOI: https://doi.org/10.1074/jbc.M114.591958
- Primary Citation of Related Structures:
4QFX, 4QFY, 4QFZ, 4QG0, 4QG1, 4QG2, 4QG4 - PubMed Abstract:
Sterile α 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) 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 tetramerization and the structure of SAMHD1 catalytic core 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.
Organizational Affiliation:
From the Department of Structural Biology and Pittsburgh Center for HIV-Host Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
