Review of Apobec Enzymes

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The Current Structural and Functional Understanding of APOBEC Deaminases (Running Title: Structural Insights for APOBEC Deaminase)

Keywords: APOBEC, cytidine deaminase, Viral Infectivity Factor (Vif), Human Immunodeficiency Virus (HIV), DNA deamination, RNA editing


The Apolipoprotein B mRNA-editing Enzyme Catalytic polypeptide family of cytidine deaminases has emerged as an intensively studied field as a result of their important biological functions. These enzymes are involved in lipid metabolism, antibody diversification and the inhibition of retrotransposons, retroviruses and some DNA viruses. The APOBEC proteins function in these roles by deaminating single-stranded (ss) DNA or RNA. There are two high resolution crystal structures available for the APOBEC family, Apo2 and the C-terminal catalytic domain (CD2) of Apo3G or Apo3G-CD2 [1,2]. Additionally, the structure of Apo3G-CD2 has also been determined using NMR [3-5]. A detailed structural analysis of the APOBEC proteins and a comparison to other zinc-coordinating deaminases can facilitate our understanding of how APOBEC proteins bind nucleic acids, recognize substrates, and form oligomers. Here we review the recent development of structural and functional studies that apply to Apo3G as well as the APOBEC deaminase family.


The Apolipoprotein B mRNA-editing Enzyme Catalytic polypeptide (APOBEC) family of cytidine deaminases consists of eleven members: APOBEC-1 (Apo1), APOBEC-2 (Apo2), Activation Induced Cytidine Deaminase (AID), APOBEC-3A, -3B, -3C, -3DE, -3F, -3G, -3H (Apo3A-H) and APOBEC-4 (Apo4). These enzymes catalyze deamination of cytidine to uracil on single stranded (ss) DNA or RNA. The APOBEC enzymes have a catalytic domain defined by a conserved cytidine deamination sequence motif (H-X-E-X23-28-P-C-X-C) [6]. The residues within the motif coordinate a Zn atom, which carries out the nucleophilic attack in the cytidine deamination reaction. Four APOBEC enzymes, Apo3G, Apo3F, Apo3B and Apo3DE, are composed of two catalytic domains containing the residues necessary for catalysis. Current data indicate that the N-terminal domains (CD1) of Apo3G and Apo3F are enzymatically inactive and that the C-terminal catalytic domains (CD2) are active [7-11]. Both domains of Apo3B are enzymatically active [12]. The reason why some APOBEC domains are inactive is not understood. For all of the APOBEC proteins, excluding Apo2 and Apo4, catalytic activity has been observed and biological roles have been determined.

Overview of the Biological Roles of the APOBEC Family

The founding member of the APOBEC family, Apo1, has a well characterized role in lipid metabolism [13-15]. Apo1 deaminates the 6666 cytidine in the apolipoprotein B (apoB) mRNA, thereby creating two isoforms of the apoB protein. The apoB100 (full length) and apoB48 (truncated) are used to transport cholesterol and triglyceride, respectively, in the blood [15]. Although Apo1 can deaminate ssDNA, the apoB mRNA is its only known substrate in vivo [16]. Apo1 is the only APOBEC protein known to deaminate a RNA substrate. Further, Apo1 RNA deamination requires a cellular co-factor [17].

Another APOBEC protein, AID, is required for antibody affinity maturation [18]. In activated germinal center B cells, AID presumably initiates somatic hypermutation (SHM) by introducing dC ( dU mutations in the VDJ region of the Immunoglobulin (Ig) gene [19]. The Ig gene hypermutation enhances the ability of the antibody to bind and neutralize the antigen. The biochemical characterization of AID deamination activity demonstrates that AID specifically acts on ssDNA substrates and targets cytidines in SHM hotspot sequence motifs (WRCY) observed in vivo [20-22]. Transcription of the Ig gene provides a ssDNA substrate for AID [23]. AID also initiates class switch recombination (CSR), which enables the expression of different antibody isotypes (for...
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