4qg0
Crystal structure of the tetrameric dGTP/dUTP-bound SAMHD1 (RN206) mutant catalytic core
Structural highlights
DiseaseSAMH1_HUMAN Defects in SAMHD1 are the cause of Aicardi-Goutieres syndrome type 5 (AGS5) [MIM:612952. A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.[1] [2] Defects in SAMHD1 are the cause of chilblain lupus type 2 (CHBL2) [MIM:614415. A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.[3] FunctionSAMH1_HUMAN Putative nuclease involved in innate immune response by acting as a negative regulator of the cell-intrinsic antiviral response. May play a role in mediating proinflammatory responses to TNF-alpha signaling.[4] [5] Publication Abstract from PubMedSterile 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. Structural basis of allosteric activation of Sterile Alpha Motif and Histidine-Aspartate Domain containing protein 1 (SAMHD1) by nucleoside triphosphates.,Koharudin LM, Wu Y, DeLucia M, Mehrens J, Gronenborn AM, Ahn J J Biol Chem. 2014 Oct 6. pii: jbc.M114.591958. PMID:25288794[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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