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首页> 外文期刊>Journal of Molecular Biology >Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins
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Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins

机译：十一人类apobec蛋白的胞苷和甲基胞苷脱胺的家庭范围对比分析

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Abstract Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins are a family of cytidine deaminases involved in various important biological processes such as antibody diversification/maturation, restriction of viral infection, and generation of somatic mutations. Catalytically active APOBEC proteins execute their biological functions mostly through deaminating cytosine (C) to uracil on single-stranded DNA/RNA. Activation-induced cytidine deaminase, one of the APOBEC members, was reported to deaminate methylated cytosine (mC) on DNA, and this mC deamination was proposed to be involved in the demethylation of mC for epigenetic regulation. The mC deamination activity is later demonstrated for APOBEC3A (A3A) and more recently for APOBEC3B and APOBEC3H (A3H). Despite extensive studies on APOBEC proteins, questions regarding whether the rest of APOBEC members have any mC deaminase activity and what are the relative deaminase activities for each APOBEC member remain unclear. Here, we performed a family-wide analysis of deaminase activities on C and mC by using purified recombinant proteins for 11 known human APOBEC proteins under similar conditions. Our comprehensive analyses revealed that each APOBEC has unique deaminase activity and selectivity for mC. A3A and A3H showed distinctively high deaminase activities on C and mC with relatively high selectivity for mC, whereas six other APOBEC members showed relatively low deaminase activity and selectivity for mC. Our mutational analysis showed that loop-1 of A3A is responsible for its high deaminase activity and selectivity for mC. These findings extend our understanding of APOBEC family proteins that have important roles in diverse biological functions and in genetic mutations. Graphical Abstract Display Omitted Highlights ? Comparative study of the in vitro activities on cytidine (C) and methylcytidine (mC) deamination of the APOBEC protein family was conducted. ? Eight of the nine C deaminase active APOBECs show deaminase activity on mC. ? The top three APOBECs with the highest C deamination activity are in the order of A3A, A3H, and A3C. ? The top three APOBECs with the highest mC deamination activity are in the order of A3A, A3H, and A3B. ? The top three APOBECs with the highest mC selectivity factor are in the order of A3H, A3A, and activation-induced cytidine deaminase. The lowest mC selectivity factor is observed in A3C. ? Residues on loop 1 of A3A contribute critically to the high deaminase activity and high mC selectivity.
机译：摘要载脂蛋白B mRNA编辑酶，催化多肽状（Apobec）蛋白是一种胞嘧啶脱胺酶的家族，涉及各种重要的生物方法，例如抗体多样化/成熟，病毒感染的限制以及体细胞突变的产生。催化活性Apobec蛋白主要通过在单链DNA / RNA上将胞嘧啶（C）掺杂至尿嘧啶来执行它们的生物学函数。据报道，活化诱导的胞苷脱氨酶，其中一种apobec构件是在DNA上携带甲基化胞嘧啶（MC），并且提出该MC脱氨基参与MC的去甲基化以进行表观遗传调控。稍后对Apobec3A（A3A）和最近进行Apobec3B和Apobec3H（A3H）的MC脱胺活性。尽管对Apobec蛋白质进行了广泛的研究，关于Apobec成员的其余部分是否具有MC脱氨酶活性，并且每个APOBEC成员的相对脱氨基酶活性仍然不清楚。这里，我们通过在类似条件下使用纯化的重组蛋白在C和MC上对C和MC进行的全群酶活性分析。我们的综合分析显示，每个Apobec都有独特的脱氨酶活性和MC的选择性。 A3A和A3H在C和MC上显示出明显高的脱氨酶活性，具有相对较高的MC选择性，而六种其他apobec构件显示出相对低的脱氨酶活性和用于MC的选择性。我们的突变分析表明，A3A的环-1负责其高脱氨酶活性和MC的选择性。这些发现扩展了我们对具有重要作用和遗传突变具有重要作用的Apobec系列蛋白的理解。图形抽象显示省略了亮点？进行了胞苷（C）和甲基胞苷（MC）脱胺的体外活性的对比研究。还是八个九个C脱氨酶活性Apobecs在MC上显示脱氨酶活性。还是具有最高C脱胺活动的前三个apobec是A3A，A3H和A3C的顺序。还是具有最高MC脱胺活动的前三个apobec是A3A，A3H和A3B的顺序。还是具有最高MC选择性因子的前三个apobec是A3H，A3A和活化诱导的胞苷脱氨酶的顺序。在A3C中观察到最低MC选择性因子。还是A3a的环1上的残基致力于高脱氨酶活性和高MC选择性。

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