Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEOG
Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEOG
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DOI：
10.1073/pnas.0502440102
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发表时间：
2005-08-09
影响因子：
11.1
通讯作者：
Yu, XF
中科院分区：
文献类型：
--
作者：
Luo, K;Xiao, ZX;Yu, XF
Cullin-Ring E3泛素连接酶的目标底物泛素依赖，蛋白酶体介导的降解和调节关键的细胞过程。这些cullins通过特定的接头分子与细胞底物受体蛋白组装。含有F-box和bc -box的受体分别使用Skp1、ElonginB和ElonginC作为接头来募集Cul1/Cul7和Cul2/Cul5。目前，BC-box-containing受体的Cul2和Cul5特异性的决定因素尚未明确。在这里，我们证明灵长类慢病毒Vif（病毒粒子感染因子）蛋白代表以前未被表征的底物受体蛋白，其中包含不同的BC-box基序。这些分子选择性地与Cul5-E3连接酶结合，抑制自身胞苷脱氨酶APOBEC3G的抗病毒活性。先前未被识别的HX5CX17-18CX3-5H基序在所有灵长类慢病毒Vif蛋白中高度保守，被发现对Vif- cul5 - e3连接酶的选择性组装和活性至关重要。缺乏HCCH基序的非灵长类慢病毒Vif蛋白与Cul5的相互作用减少。这些数据表明，除了靶蛋白特异性外，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。这些病毒底物受体分子通过不同的机制从细胞蛋白中招募Cul5，这一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中不存在于细胞蛋白中的基序也可能成为开发创新疗法的靶点。
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 HX5CX17-18CX3-5H 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.