Divergence in dimerization and activity of primate APOBEC3C
Divergence in dimerization and activity of primate APOBEC3C
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灵长类动物 APOBEC3C 二聚化和活性的差异
DOI：
10.1101/2021.07.13.452235
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Cisneros, G. Andres
中科院分区：
文献类型：
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作者：
Gaba, A.;Hix, Mark A.;Suhail, Sana;Flath, Ben;Boysan, Brock;Williams, Danielle R.;Pelletier, Tomas;Emerman, Michael;Morcos, Faruck;Cisneros, G. Andres
单链DNA胞苷脱氨酶的APOBEC 3（A3）家族是在不存在导致其降解的Vif蛋白的情况下抑制慢病毒（例如HIV-1）的宿主限制性因子。HIV-1（−）DNA中的胞苷脱氨基形成尿嘧啶，当尿嘧啶用作（+）DNA合成的模板时，尿嘧啶会导致失活突变。对于APOBEC 3C（A3 C），黑猩猩和大猩猩的直系同源物比人类A3 C更有活性，我们确定来自恒河猴（rh）的旧世界猴A3 C对HIV-1没有活性。生物化学，病毒学和协同进化分析结合分子动力学模拟表明，促进rhA 3C抗病毒活性所需的关键氨基酸，44，45和144，也促进二聚化和变化的动态循环1，酶活性位点附近。虽然rhA 3C的强制进化导致了类似的二聚体接口与人类A3 C，关键的氨基酸接触是不同的。总的来说，我们的研究结果确定了为什么rhA 3C比人A3 C活性低的基础，并建立了二聚化和活性增加的氨基酸网络。基于确定旧大陆猴抗病毒活性的关键氨基酸的鉴定，我们预测其他旧大陆猴A3 C不赋予抗慢病毒活性，尽管固定了原始人A3 C活性所需的关键残基。总体而言，A3 C二聚化接口的共同进化分析也提供了一个基础，从它来分析其他A3家庭成员的二聚化接口。
The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (−)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and we determined that Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity, 44, 45, and 144, also promoted dimerization and changes to the dynamics of loop 1, near the enzyme active site. Although forced evolution of rhA3C resulted in a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C and establish the amino acid network for dimerization and increased activity. Based on identification of the key amino acids determining Old World Monkey antiviral activity we predict that other Old World Monkey A3Cs did not impart anti-lentiviral activity, despite fixation of a key residue needed for hominid A3C activity. Overall, the coevolutionary analysis of the A3C dimerization interface presented also provides a basis from which to analyze dimerization interfaces of other A3 family members.