Cytidine deamination and resistance to retroviral infection: towards a structural understanding of the APOBEC proteins.
The human apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, or hA3G) protein, provides cells with an intracellular antiretroviral activity that is associated with the hypermutation of viral DNA through cytidine deamination. Indeed, hA3G belongs to a family of vertebrate proteins that contain one or two copies of a signature sequence motif unique to cytidine deaminases (CTDAs). We have constructed secondary structure models of the APOBEC proteins through a combination of structure prediction and subsequent alignment with nucleotide CTDAs whose structures have been solved to high resolution. Secondary structure elements common to all CTDAs are predicted, in addition to structural features that are apparently unique to the APOBEC family of proteins. Most notably, a putative looped-out helix abuts an amino acid that modulates the susceptibility of A3G proteins to the antagonistic action of the human and simian immunodeficiency virus (HIV and SIV) Vif proteins. Using the structure models as a guide, we reflect on mutagenesis studies of the APOBEC1 (A1), hA3G and activation induced deaminase (AID) proteins, with emphasis on the determinants of cytidine deamination and antiviral activities.
Huthoff
Hendrik
H
Department of Infectious Diseases, Guy's, King's and St Thomas' School of Medicine, King's College London, GKT Guy's Hospital, London SE1 9RT, UK.
Malim
Michael H
MH
D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003562:Cytidine / Q000378:metabolism; D003564:Cytidine Deaminase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009700:Nucleoside Deaminases; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012097:Repressor Proteins
D000998:Antiviral Agents; D011506:Proteins; D012097:Repressor Proteins; D003562:Cytidine; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase