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Browsing Faculty Research and Publications by Subject "Active oxygen"
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- ItemFunctionality of redox-active crysteines is required for restriction of retroviral replication by SAMHD1(Cell Press, 2018) Wang, Zhonghua; Bhattacharya, Akash; White, Tommy; Buffone, Cindy; McCabe, Aine; Nguyen, Laura A.; Shepard, Caitlin N.; Pardo, Sammy; Kim, Baek; Weintraub, Susan T.; Demeler, Borries; Diaz-Griffero, Felipe; Ivanov, Dmitri N.SAMHD1 is a dNTP triphosphohydrolase (dNTPase)that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1is a redox-sensitive enzyme and identify threeredox-active cysteines within the protein: C341,C350, and C522. The three cysteines reside nearone another and the allosteric nucleotide bindingsite. Mutations C341S and C522S abolish the abilityof SAMHD1 to restrict HIV replication, whereas theC350S mutant remains restriction competent. TheC522S mutation makes the protein resistant to inhibi-tion by hydrogen peroxide but has no effect onthe tetramerization-dependent dNTPase activity ofSAMHD1in vitroor on the ability of SAMHD1 todeplete cellular dNTPs. Our results reveal that enzy-matic activation of SAMHD1 via nucleotide-depen-dent tetramerization is not sufficient for the estab-lishment of the antiviral state and that retroviralrestriction depends on the ability of the protein to un-dergo redox transformations.