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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G
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Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G

机译：灵长类慢病毒病毒体感染因子是通过HCCH基序与cullin 5-E3连接酶组装的底物受体，从而抑制APOBEC3G

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摘要

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 Hx_5Cx_(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.
机译：Cullin-Ring E3泛素连接酶靶向底物进行泛素依赖性蛋白酶体介导的降解并调节关键的细胞过程。这些cullins通过特定的衔接子分子与细胞底物受体蛋白组装在一起。含有F-box和BC-box的受体使用Skp1，ElonginB和ElonginC作为衔接子分别募集Cul1，Cul7和Cul2 / Cul5。目前，关于含BC-box的受体的Cul2与Cul5特异性的决定因素还不清楚。在这里，我们证明了灵长类慢病毒Vif（病毒体感染因子）蛋白代表了以前未表征的底物受体蛋白，其中包含不同的BC-box图案。这些分子与Cul5-E3连接酶选择性组装，以抑制自体胞苷脱氨酶APOBEC3G的抗病毒活性。发现在所有灵长类慢病毒Vif蛋白中高度保守的以前无法识别的Hx_5Cx_（17-18）Cx_（3-5）H基序对于Vif-Cul5-E3连接酶的选择性组装和活性至关重要。缺少此HCCH主题的非灵长类慢病毒Vif蛋白显示与Cul5的相互作用减少。这些数据表明，除靶蛋白特异性外，底物受体蛋白在cullin选择和cullin-Ring E3连接酶的功能组装中也起着重要作用。这些通过与细胞蛋白不同的机制募集Cul5的病毒底物受体分子的发现，可能有助于鉴定通过Cul5-E3连接酶调节细胞功能的其他细胞因子。 Vif中细胞蛋白中缺少的基序也可能成为创新疗法发展的目标。

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