Abstract:
:Cullin-Ring E3 ubiquitin ligases target substrates for ubiquitin-dependent, proteasome-mediated degradation and regulate critical cellular processes. These cullins assemble with cellular substrate receptor proteins through specific adaptor molecules. F-box- and BC-box-containing receptors use Skp1, ElonginB, and ElonginC as adaptors to recruit Cul1/Cul7 and Cul2/Cul5, respectively. At present, the determinants of Cul2 vs. Cul5 specificity for the BC-box-containing receptors are poorly defined. Here, we demonstrate that primate lentiviral Vif (virion infectivity factor) proteins represent previously uncharacterized substrate receptor proteins that contain divergent BC-box motifs. These molecules selectively assemble with a Cul5-E3 ligase to suppress the antiviral activity of autologous cytidine deaminase APOBEC3G. A previously unrecognized Hx5Cx(17-18)Cx(3-5)H motif that is highly conserved among all primate lentiviral Vif proteins was found to be critical for the selective assembly and activity of Vif-Cul5-E3 ligase. Non-primate lentiviral Vif proteins, which lack this HCCH motif, displayed reduced interaction with Cul5. These data suggest that in addition to target protein specificity, substrate receptor proteins play important roles in cullin selection and functional assembly of cullin-Ring E3 ligases. The discovery of these viral substrate receptor molecules that recruit Cul5 through distinct mechanisms from cellular proteins may facilitate the identification of additional cellular factors that regulate cellular functions through Cul5-E3 ligase. Motifs in Vif that are absent from cellular proteins could also be targets for the development of innovative therapeutics.
journal_name
Proc Natl Acad Sci U S Aauthors
Luo K,Xiao Z,Ehrlich E,Yu Y,Liu B,Zheng S,Yu XFdoi
10.1073/pnas.0502440102keywords:
subject
Has Abstractpub_date
2005-08-09 00:00:00pages
11444-9issue
32eissn
0027-8424issn
1091-6490pii
0502440102journal_volume
102pub_type
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