Article

The APOBEC-2 crystal structure and functional implications for the deaminase AID

Molecular and Computational Biology, University of Southern California Los Angeles, California 90089, USA.
Nature (Impact Factor: 42.35). 02/2007; 445(7126):447-51. DOI: 10.1038/nature05492
Source: PubMed

ABSTRACT APOBEC-2 (APO2) belongs to the family of apolipoprotein B messenger RNA-editing enzyme catalytic (APOBEC) polypeptides, which deaminates mRNA and single-stranded DNA. Different APOBEC members use the same deamination activity to achieve diverse human biological functions. Deamination by an APOBEC protein called activation-induced cytidine deaminase (AID) is critical for generating high-affinity antibodies, and deamination by APOBEC-3 proteins can inhibit retrotransposons and the replication of retroviruses such as human immunodeficiency virus and hepatitis B virus. Here we report the crystal structure of APO2. APO2 forms a rod-shaped tetramer that differs markedly from the square-shaped tetramer of the free nucleotide cytidine deaminase, with which APOBEC proteins share considerable sequence homology. In APO2, two long alpha-helices of a monomer structure prevent the formation of a square-shaped tetramer and facilitate formation of the rod-shaped tetramer via head-to-head interactions of two APO2 dimers. Extensive sequence homology among APOBEC family members allows us to test APO2 structure-based predictions using AID. We show that AID deamination activity is impaired by mutations predicted to interfere with oligomerization and substrate access. The structure suggests how mutations in patients with hyper-IgM-2 syndrome inactivate AID, resulting in defective antibody maturation.

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    • "Structural studies of the C-terminal CDA of A3G (Chen et al., 2008; Furukawa et al., 2009; Harjes et al., 2009; Holden et al., 2008; Zhang et al., 2007) and the single domain APOBEC2 protein (Prochnow et al., 2007) revealed that, the CDA consists of five β strands flanked by an α-helix on each side plus appropriate connecting loops. "
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    • ").Inthesemice,theproportionofmutations thatsegregatedwithRGYW/WRCYwasmorethan 44%higherthaninC57BL/6mice:41.2vs.28.6% (p,0.002).RGYW/WRCYcontainstheWRCmotif anditscomplementGYW,whicharepreferentially targetedbyAIDinvitro,indicatingthattheintrinsic SHMhotspotowesmuchtotheinherentsequence specificityofAIDitself[52].SinceAIDcanform dimers[71] [72],partiallyoverlappingWRConopposite strandswouldfacilitatebindingbytwosubunits ofanAIDdimer. "
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    Autoimmunity 03/2009; 42(2):89-103. DOI:10.1080/08916930802629554 · 2.75 Impact Factor
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    • "In spite of the great attention to the APOBEC/AID protein family, the structural knowledge on this family is quite limited. The structure of APOBEC2 was reported last year (Prochnow et al, 2007), but APOBEC2 does not possess enzymatic activity. APOBEC3G is composed of 384 residues and possesses two consensus cytidine deaminase motifs of the zinc-finger type, His-X-Glu-X 27-28 -Pro-Cys-X 2 -Cys, in its N-and C-terminal domains (Harris and Liddament, 2004). "
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