title: Characterization of conserved motifs in HIV-1 Vif required for APOBEC3G and APOBEC3F interaction.
abstract: Apolipoprotein B mRNA-editing catalytic polypeptide-like 3G (APOBEC3G, or A3G) and related cytidine deaminases such as apolipoprotein B mRNA-editing catalytic polypeptide-like 3F (APOBEC3F, or A3F) are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus (HIV)-1 requires suppression of multiple cytidine deaminases by Vif. HIV-1 Vif suppresses various APOBEC3 proteins through a common mechanism by recruiting Cullin5, ElonginB, and ElonginC E3 ubiquitin ligase to induce target protein polyubiquitination and proteasome-mediated degradation. Domains in Vif that mediate APOBEC3 recognition have not been fully characterized. In the present study, we identified a VxIPLx(4-5)LxPhix(2)YWxL motif in HIV-1 Vif, which is required for efficient interaction between Vif and A3G, Vif-mediated A3G degradation and virion exclusion, and functional suppression of the A3G antiviral activity. Amino acids 52 to 72 of HIV-1 Vif (including the VxIPLx(4-5)LxPhix(2)YWxL motif) alone could mediate interaction with A3G, and this interaction was abolished by mutations of two hydrophobic amino acids in this region. We have also observed that a Vif mutant was ineffective against A3G, yet it retained the ability to interact with Cullin5-E3 ubiquitin complex and A3G, suggesting that interaction with A3G is necessary but not sufficient to inhibit its antiviral function. Unlike the previously identified motif of HIV-1 Vif amino acids 40 to 44, which is only important for A3G suppression, the VxIPLx(4-5)LxPhix(2)YWxL motif is also required for efficient A3F interaction and suppression. On the other hand, another motif, TGERxW, of HIV-1 Vif amino acids 74 to 79 was found to be mainly important for A3F interaction and inhibition. Both the VxIPLx(4-5)LxPhix(2)YWxL and TGERxW motifs are highly conserved among HIV-1, HIV-2, and various simian immunodeficiency virus Vif proteins. Our data suggest that primate lentiviral Vif molecules recognize their autologous APOBEC3 proteins through conserved structural features that represent attractive targets for the development of novel inhibitors.
authors.affiliation: Second Affiliated Hospital, Cancer Institute, School of Medicine, Zhejiang University, Zhejiang, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: He
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.forename: Gongying
authors.initials: G
authors.lastname: Chen
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Xu
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D000071480:APOBEC-3G Deaminase; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D017124:Conserved Sequence; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010455:Peptides; D054320:vif Gene Products, Human Immunodeficiency Virus; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase