Wolfe Aaron D, Li Shuxing, Goedderz Cody, Chen Xiaojiang S
Genetics, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
NAR Cancer. 2020 Dec;2(4):zcaa027. doi: 10.1093/narcan/zcaa027. Epub 2020 Oct 9.
APOBEC1 (APO1), a member of AID/APOBEC nucleic acid cytosine deaminase family, can edit apolipoprotein B mRNA to regulate cholesterol metabolism. This APO1 RNA editing activity requires a cellular cofactor to achieve tight regulation. However, no cofactors are required for deamination on DNA by APO1 and other AID/APOBEC members, and aberrant deamination on genomic DNA by AID/APOBEC deaminases has been linked to cancer. Here, we present the crystal structure of APO1, which reveals a typical APOBEC deaminase core structure, plus a unique well-folded C-terminal domain that is highly hydrophobic. This APO1 C-terminal hydrophobic domain (A1HD) interacts to form a stable dimer mainly through hydrophobic interactions within the dimer interface to create a four-stranded β-sheet positively charged surface. Structure-guided mutagenesis within this and other regions of APO1 clarified the importance of the A1HD in directing RNA and cofactor interactions, providing insights into the structural basis of selectivity on DNA or RNA substrates.
载脂蛋白B mRNA编辑酶催化多肽1（APO1）是AID/APOBEC核酸胞嘧啶脱氨酶家族的成员之一，可对载脂蛋白B mRNA进行编辑以调节胆固醇代谢。这种APO1 RNA编辑活性需要一种细胞辅因子来实现严格调控。然而，APO1和其他AID/APOBEC成员在DNA上进行脱氨基作用时不需要辅因子，并且AID/APOBEC脱氨酶在基因组DNA上的异常脱氨基作用与癌症有关。在此，我们展示了APO1的晶体结构，该结构揭示了一个典型的APOBEC脱氨酶核心结构，以及一个独特的折叠良好的高度疏水的C末端结构域。这个APO1 C末端疏水结构域（A1HD）相互作用，主要通过二聚体界面内的疏水相互作用形成稳定的二聚体，从而形成一个带正电荷的四链β-折叠表面。在APO1的这个区域和其他区域进行的结构导向诱变阐明了A1HD在指导RNA和辅因子相互作用中的重要性，为DNA或RNA底物选择性的结构基础提供了见解。
