Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands

Abstract

The 11-member APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of zinc-dependent cytidine deaminases bind to RNA and single-stranded DNA (ssDNA) and, in specific contexts, modify select (deoxy)cytidines to (deoxy)uridines. In this review, we describe advances made through high-resolution co-crystal structures of APOBECs bound to mono- or oligonucleotides that reveal potential substrate-specific binding sites at the active site and non-sequence-specific nucleic acid binding sites distal to the active site. We also discuss the effect of APOBEC oligomerization on functionality. Future structural studies will need to address how ssDNA binding away from the active site may enhance catalysis and the mechanism by which RNA binding may modulate catalytic activity on ssDNA.

Highlights

APOBEC proteins catalyze deamination of cytidine or deoxycytidine in either a sequence-specific or semi-specific manner on either DNA or RNA.

APOBECs each possess the cytidine deaminase core fold, but sequence and structural differences among loops surrounding the zinc-dependent active site impart differences in sequence-dependent target preferences, binding affinity, catalytic rate, and regulation of substrate access to the active site among the 11 family members.

APOBECs also regulate the deamination reaction through additional nucleic acid substrate binding sites located within surface grooves or patches of positive electrostatic potential that are distal to the active site but may do so nonspecifically.

Binding of nonsubstrate RNA and RNA-mediated oligomerization by APOBECs that deaminate ssDNA downregulates catalytic activity but also controls APOBEC subcellular or virion localization.

The presence of a second, though noncatalytic, cytidine deaminase domain for some APOBECs and the ability of some APOBECs to oligomerize add additional molecular surfaces for positive or negative regulation of catalysis through nucleic acid binding.