Identification of a critical T(Q/D/E)x5ADx2(I/L) motif from primate lentivirus Vif proteins that regulate APOBEC3G and APOBEC3F neutralizing activity.
Primate lentiviruses are unique in that they produce several accessory proteins to help in the establishment of productive viral infection. The major function of these proteins is to clear host resistance factors that inhibit viral replication. Vif is one of these proteins. It functions as an adaptor that binds to the cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) and bridges them to a cullin 5 (Cul5) and elongin (Elo) B/C E3 ubiquitin ligase complex for proteasomal degradation. So far, 11 discontinuous domains in Vif have been identified that regulate this degradation process. Here we report another domain, T(Q/D/E)x(5)ADx(2)(I/L), which is located at residues 96 to 107 in the human immunodeficiency virus type 1 (HIV-1) Vif protein. This domain is conserved not only in all HIV-1 subtypes but also in other primate lentiviruses, including HIV-2 and simian immunodeficiency virus (SIV), which infects rhesus macaques (SIVmac) and African green monkeys (SIVagm). Mutations of the critical residues in this motif seriously disrupted Vif's neutralizing activity toward both A3G and A3F. This motif regulates Vif interaction not only with A3G and A3F but also with Cul5. When this motif was inactivated in the HIV-1 genome, Vif failed to exclude A3G and A3F from virions, resulting in abortive HIV replication in nonpermissive human T cells. Thus, T(Q/D/E)x(5)ADx(2)(I/L) is a critical functional motif that directly supports the adaptor function of Vif and is an attractive target for inhibition of Vif function.
Dang
Ying
Y
Departments of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824-4320, USA.
Wang
Xiaojun
X
York
Ian A
IA
Zheng
Yong-Hui
YH
D000071480:APOBEC-3G Deaminase; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D016180:Lentivirus Infections / Q000821:virology; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase