Abstract of the PDB Structure's related Publication:
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.
Apolipoprotein B mRNA editing enzyme catalytic subunit 1 is the catalytic subunit of a multiprotein editosome complex that edits (apo) B mRNA. The modification of apoB mRNA entails neither RNA guides nor cofactors, appearing as different from an insertional editing process. A bona fide uridine is synthesized in situ without the cleavage the RNA backbone (Lau et al. 1997 ). The classification of (apo)B mRNA is classified as substitutional or as modification editing. This editing implies the modification of a glutamine (Q) codon CAA to a stop UAA codon.
Neurofibromatosis type I (NFI) tumor suppressor harbors a mooring sequence that is required for apoB mRNA editing. Unlike apoB NFI editing does not demonstrate any rate limiting quantity dependence on APOBEC1 quantity. This suggests that different trans-acting factors may be involved in the two editing processes (Skuse et al. 1996 ).
NAT1 has been observed as a new editing target for APOBEC1. NAT1 appears ubiquitously expressed and extraordinarily conserved among species. In mouse and rabbit livers, NAT1 is extensively modified by APOBEC1 at multiple sites. This entails the alteration of multiple encoded amino acids, the generation of multiple stop codons, and finally resulting in starkly reduced levels of NAT1 levels in the mouse liver. NAT1 aberrant modification could contribute to potent oncogenesis induced by the overexpression of APOBEC1 (Yamanaka et al. 1997 ).
Sequence analyses of rpoB demonstrate that APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis given the presence of AID/APOBEC mutational signature in esophageal adenocarcinoma (Saraconi et al. 2014 )