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Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1.
Cell Reports ( IF 7.5 ) Pub Date : 2018-07-24 , DOI: 10.1016/j.celrep.2018.06.090
Zhonghua Wang 1 , Akash Bhattacharya 1 , Tommy White 2 , Cindy Buffone 2 , Aine McCabe 2 , Laura A Nguyen 3 , Caitlin N Shepard 3 , Sammy Pardo 1 , Baek Kim 4 , Susan T Weintraub 1 , Borries Demeler 1 , Felipe Diaz-Griffero 2 , Dmitri N Ivanov 1
Cell Reports ( IF 7.5 ) Pub Date : 2018-07-24 , DOI: 10.1016/j.celrep.2018.06.090
Zhonghua Wang 1 , Akash Bhattacharya 1 , Tommy White 2 , Cindy Buffone 2 , Aine McCabe 2 , Laura A Nguyen 3 , Caitlin N Shepard 3 , Sammy Pardo 1 , Baek Kim 4 , Susan T Weintraub 1 , Borries Demeler 1 , Felipe Diaz-Griffero 2 , Dmitri N Ivanov 1
Affiliation
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SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1 is a redox-sensitive enzyme and identify three redox-active cysteines within the protein: C341, C350, and C522. The three cysteines reside near one another and the allosteric nucleotide binding site. Mutations C341S and C522S abolish the ability of SAMHD1 to restrict HIV replication, whereas the C350S mutant remains restriction competent. The C522S mutation makes the protein resistant to inhibition by hydrogen peroxide but has no effect on the tetramerization-dependent dNTPase activity of SAMHD1 in vitro or on the ability of SAMHD1 to deplete cellular dNTPs. Our results reveal that enzymatic activation of SAMHD1 via nucleotide-dependent tetramerization is not sufficient for the establishment of the antiviral state and that retroviral restriction depends on the ability of the protein to undergo redox transformations.
中文翻译：
SAMHD1限制逆转录病毒复制所需要的氧化还原活性半胱氨酸的功能。
SAMHD1是一种dNTP三磷酸水解酶（dNTPase），可破坏非循环免疫细胞子集中的逆转录病毒复制。在这里，我们显示SAMHD1是一种对氧化还原敏感的酶，并在蛋白质中鉴定出三个氧化还原活性半胱氨酸：C341，C350和C522。这三个半胱氨酸彼此靠近，并且相互之间存在变构核苷酸结合位点。突变C341S和C522S消除了SAMHD1限制HIV复制的能力，而C350S突变体仍然具有限制性能力。C522S突变使蛋白质具有抗过氧化氢抑制作用，但对SAMHD1的四聚化依赖性dNTPase活性没有影响，也对SAMHD1消耗细胞dNTPs的能力没有影响。
更新日期：2018-07-25
中文翻译：
SAMHD1限制逆转录病毒复制所需要的氧化还原活性半胱氨酸的功能。
SAMHD1是一种dNTP三磷酸水解酶（dNTPase），可破坏非循环免疫细胞子集中的逆转录病毒复制。在这里，我们显示SAMHD1是一种对氧化还原敏感的酶，并在蛋白质中鉴定出三个氧化还原活性半胱氨酸：C341，C350和C522。这三个半胱氨酸彼此靠近，并且相互之间存在变构核苷酸结合位点。突变C341S和C522S消除了SAMHD1限制HIV复制的能力，而C350S突变体仍然具有限制性能力。C522S突变使蛋白质具有抗过氧化氢抑制作用，但对SAMHD1的四聚化依赖性dNTPase活性没有影响，也对SAMHD1消耗细胞dNTPs的能力没有影响。
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