Molecular and Computational Biology, Departments of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
School of Engineering and Technology, CQUniversity, Sydney, NSW, 2000, Australia.
Nat Commun. 2024 Oct 10;15(1):8773. doi: 10.1038/s41467-024-52671-1.
APOBEC3G, part of the AID/APOBEC cytidine deaminase family, is crucial for antiviral immunity. It has two zinc-coordinated cytidine-deaminase domains. The non-catalytic N-terminal domain strongly binds to nucleic acids, whereas the C-terminal domain catalyzes C-to-U editing in single-stranded DNA. The interplay between the two domains is not fully understood. Here, we show that DNA editing function of rhesus macaque APOBEC3G on linear and hairpin loop DNA is enhanced by AA or GA dinucleotide motifs present downstream in the 3'-direction of the target-C editing sites. The effective distance between AA/GA and the target-C sites is contingent on the local DNA secondary structure. We present two co-crystal structures of rhesus macaque APOBEC3G bound to ssDNA containing AA and GA, revealing the contribution of the non-catalytic domain in capturing AA/GA DNA. Our findings elucidate the molecular mechanism of APOBEC3G's cooperative function, which is critical for its antiviral role and its contribution to mutations in cancer genomes.
APOBEC3G 是 AID/APOBEC 胞苷脱氨酶家族的一部分，对抗病毒免疫至关重要。它有两个锌协调的胞苷脱氨酶结构域。非催化的 N 端结构域与核酸强烈结合，而 C 端结构域催化单链 DNA 中的 C 到 U 编辑。两个结构域之间的相互作用尚未完全理解。在这里，我们表明，灵长类动物恒河猴 APOBEC3G 在线性和发夹环 DNA 上的 DNA 编辑功能通过存在于靶-C 编辑位点 3'-末端下游的 AA 或 GA 二核苷酸基序得到增强。AA/GA 与靶-C 位点之间的有效距离取决于局部 DNA 二级结构。我们提出了两种灵长类动物恒河猴 APOBEC3G 与含有 AA 和 GA 的 ssDNA 结合的共结晶结构，揭示了非催化结构域在捕获 AA/GA DNA 中的作用。我们的发现阐明了 APOBEC3G 协同功能的分子机制，这对其抗病毒作用及其对癌症基因组中突变的贡献至关重要。
