Ikeda Terumasa, Ong Eugene Boon Beng, Watanabe Nobumoto, Sakaguchi Nobuo, Maeda Kazuhiko, Koito Atsushi
Department of Retrovirology and Self-Defense, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Penang, Malaysia.
Sci Rep. 2016 Jan 7;6:19035. doi: 10.1038/srep19035.
APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV-1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C-terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1.
兔形目动物和啮齿动物的载脂蛋白B mRNA编辑酶催化多肽1（A1）蛋白对HIV-1具有脱氨酶依赖性限制活性，而人类A1的作用可忽略不计。为了研究A1蛋白对HIV-1限制作用的这些差异，构建了一系列结合兔和人A1的嵌合蛋白。A1的同源模型表明，它们的活性源自可能通过二聚体界面串联起作用的功能域。兔A1含有富含亮氨酸基序的C末端区域和二聚化结构域，对其抗HIV-1活性很重要。具有强抗HIV-1活性的A1嵌合体比没有抗HIV-1活性的嵌合体更有效地整合到病毒粒子中，并表现出强大的DNA诱变活性。因此，兔A1的C末端区域既参与其包装到HIV-1病毒粒子中，也参与其对病毒cDNA和基因组RNA的脱氨活性。本研究确定了A1靶标特异性的新分子机制。
