APOBEC3G limits the replication of human immunodeficiency virus type 1, other 
retroviruses, and retrotransposons. It localizes predominantly to the cytoplasm 
of cells, which is consistent with a model wherein cytosolic APOBEC3G packages 
into assembling virions, where it exerts its antiviral effect by deaminating 
viral cDNA cytosines during reverse transcription. To define the domains of 
APOBEC3G that determine cytoplasmic localization, comparisons were made with 
APOBEC3B, which is predominantly nuclear. APOBEC3G/APOBEC3B chimeric proteins 
mapped a primary subcellular localization determinant to a region within the 
first 60 residues of each protein. A panel of 25 APOBEC3G mutants, each with a 
residue replaced by the corresponding amino acid of APOBEC3B, revealed that 
several positions within this region were particularly important, with Y19D 
showing the largest effect. The mislocalization phenotype of these mutants was 
only apparent in the context of the amino-terminal half of APOBEC3G and not the 
full-length protein, suggesting the existence of an additional localization 
determinant. Indeed, a panel of five single amino acid substitutions within the 
region from amino acids 113 to 128 had little effect by themselves but, in 
combination with Y19D, two substitutions-F126S and W127A-caused full-length 
APOBEC3G to redistribute throughout the cell. The critical 
localization-determining residues were predicted to cluster on a common 
solvent-exposed surface, suggesting a model in which these two regions of 
APOBEC3G combine to mediate an intermolecular interaction that controls 
subcellular localization.