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Crystal structure of the dGTP-bound catalytic core of SAMHD1 T592V mutant
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 PubMedSAMHD1 is a cellular protein that plays key roles in HIV-1 restriction and regulation of cellular dNTP levels. Mutations in SAMHD1 are also implicated in the pathogenesis of chronic lymphocytic leukemia and Aicardi-Goutieres syndrome. The anti-HIV-1 activity of SAMHD1 is negatively modulated by phosphorylation at residue T592. The mechanism underlying the effect of phosphorylation on anti-HIV-1 activity remains unclear. SAMHD1 forms tetramers that possess deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) activity, which is allosterically controlled by the combined action of GTP and all four dNTPs. Here we demonstrate that the phosphomimetic mutation T592E reduces the stability of the SAMHD1 tetramer and the dNTPase activity of the enzyme. To better understand the underlying mechanisms, we determined the crystal structures of SAMHD1 variants T592E and T592V. While the neutral substitution T592V does not perturb the structure, the charged T592E induces large conformational changes, likely triggered by electrostatic repulsion from a distinct negatively charged environment surrounding T592. The phosphomimetic mutation results in a significant decrease in the population of active SAMHD1 tetramers and hence the dNTPase activity is substantially decreased. These results provide a mechanistic understanding of how SAMHD1 phosphorylation at residue T592 may modulate its cellular and antiviral functions. Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of T592.,Tang C, Ji X, Wu L, Xiong Y J Biol Chem. 2015 Aug 20. pii: jbc.M115.677435. PMID:26294762[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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