Show simple item record Bhattacharya, Akash Wang, Zhonghua White, Tommy Buffone, Cindy Nguyen, Laura A. Shepard, Caitlin N. Kim, Baek Demeler, Borries Diaz-Griffero, Felipe Ivanov, Dmitri N. 2021-10-13T18:28:06Z 2021-10-13T18:28:06Z 2016
dc.identifier.citation Bhattacharya, A., Wang, Z., White, T., Buffone, C., Nguyen, L. A., Shepard, C. N., Kim, B., Demeler, B., Diaz-Griffero, F., & Ivanov, D. N. (2016). Effects of T592 phosphomimetric mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect. Scientific Reports, 6, Article 31353. en_US
dc.description Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) applies en_US
dc.description.abstract SAMHD1, a dNTP triphosphohydrolase, contributes to interferon signaling and restriction of retroviral replication. SAMHD1-mediated retroviral restriction is thought to result from the depletion of cellular dNTP pools, but it remains controversial whether the dNTPase activity of SAMHD1 is sufficient for restriction. The restriction ability of SAMHD1 is regulated in cells by phosphorylation on T592. Phosphomimetic mutations of T592 are not restriction competent, but appear intact in their ability to deplete cellular dNTPs. Here we use analytical ultracentrifugation, fluorescence polarization and NMR-based enzymatic assays to investigate the impact of phosphomimetic mutations on SAMHD1 tetramerization and dNTPase activity in vitro. We find that phosphomimetic mutations affect kinetics of tetramer assembly and disassembly, but their effects on tetramerization equilibrium and dNTPase activity are insignificant. In contrast, the Y146S/Y154S dimerization-defective mutant displays a severe dNTPase defect in vitro, but is indistinguishable from WT in its ability to deplete cellular dNTP pools and to restrict HIV replication. Our data suggest that the effect of T592 phosphorylation on SAMHD1 tetramerization is not likely to explain the retroviral restriction defect and we hypothesize that enzymatic activity of SAMHD1 is subject to additional cellular regulatory mechanisms that have not yet been recapitulated in vitro. en_US
dc.language.iso en_US en_US
dc.publisher Nature Publishing en_US
dc.subject Enzyme mechanisms en_US
dc.subject Phosphomimetic mutations
dc.subject SAMHD1
dc.subject Tetramer stability
dc.subject Retroviral
dc.subject.lcsh HIV infections
dc.title Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect en_US
dc.type Article en_US
dc.publisher.faculty Arts and Science en_US
dc.publisher.department Department of Chemistry and Biochemistry en_US
dc.description.peer-review Yes en_US
dc.publisher.institution University of Texas Health Science Center at San Antonio en_US
dc.publisher.institution Albert Einstein College of Medicine en_US
dc.publisher.institution Emory School of Medicine en_US
dc.publisher.institution Kyunghee University en_US
dc.publisher.institution University of Lethbridge en_US
dc.publisher.url en_US

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