title: The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch.
abstract: OBJECTIVE
  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.
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Mauney
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: LeAnn C
authors.initials: LC
authors.lastname: Rogers
authors.affiliation: 2 Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Howard Hughes Medical Institute, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.|3 Center for Molecular Communication and Signaling , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Daniel
authors.affiliation: 4 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
authors.forename: Nelmi O
authors.initials: NO
authors.lastname: Devarie-Baez
authors.affiliation: 4 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Wu
authors.affiliation: 3 Center for Molecular Communication and Signaling , Wake Forest School of Medicine, Winston-Salem, North Carolina.|4 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Furdui
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.|3 Center for Molecular Communication and Signaling , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Poole
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
authors.affiliation: 1 Department of Biochemistry, Center for Structural Biology , Wake Forest School of Medicine, Winston-Salem, North Carolina.|3 Center for Molecular Communication and Signaling , Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollis
mesh_terms: D020134:Catalytic Domain; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry*; D000067493:Dynamic Light Scattering; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D009711:Nucleotides / Q000378:metabolism; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D000076106:SAM Domain and HD Domain-Containing Protein 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D009711:Nucleotides; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D003545:Cysteine
keywords: Aicardi–Goutieres syndrome; HIV restriction; SAMHD1; enzyme catalysis; protein oxidation; redox switch