4rxs
The structure of GTP-dTTP-bound SAMHD1
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 the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is elegantly regulated by the self-sensing ability of SAMHD1 through a novel activation mechanism. The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP.,Zhu CF, Wei W, Peng X, Dong YH, Gong Y, Yu XF Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):516-24. doi:, 10.1107/S1399004714027527. Epub 2015 Feb 26. PMID:25760601[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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