Christopher H Mauney1, LeAnn C Rogers1, Reuben S Harris2, Larry W Daniel1,3, Nelmi O Devarie-Baez4, Hanzhi Wu4, Cristina M Furdui3,4, Leslie B Poole1,3, Fred W Perrino1, Thomas Hollis1,3. 1. 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina. 2. 2 Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Howard Hughes Medical Institute, University of Minnesota , Minneapolis, Minnesota. 3. 3 Center for Molecular Communication and Signaling , Wake Forest School of Medicine, Winston-Salem, North Carolina. 4. 4 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
Abstract
AIMS: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. RESULTS: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.
AIMS: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. RESULTS: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.
Entities:
Keywords:
Aicardi–Goutieres syndrome; HIV restriction; SAMHD1; enzyme catalysis; protein oxidation; redox switch
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