Booth David S, Cheng Yifan, Frankel Alan D
Graduate Group in Biophysics, University of California, San Francisco, San Francisco, United States.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
Elife. 2014 Dec 8;3:e04121. doi: 10.7554/eLife.04121.
The HIV Rev protein routes viral RNAs containing the Rev Response Element (RRE) through the Crm1 nuclear export pathway to the cytoplasm where viral proteins are expressed and genomic RNA is delivered to assembling virions. The RRE assembles a Rev oligomer that displays nuclear export sequences (NESs) for recognition by the Crm1-Ran(GTP) nuclear receptor complex. Here we provide the first view of an assembled HIV-host nuclear export complex using single-particle electron microscopy. Unexpectedly, Crm1 forms a dimer with an extensive interface that enhances association with Rev-RRE and poises NES binding sites to interact with a Rev oligomer. The interface between Crm1 monomers explains differences between Crm1 orthologs that alter nuclear export and determine cellular tropism for viral replication. The arrangement of the export complex identifies a novel binding surface to possibly target an HIV inhibitor and may point to a broader role for Crm1 dimerization in regulating host gene expression.
HIV病毒的Rev蛋白通过Crm1核输出途径将含有Rev反应元件（RRE）的病毒RNA转运至细胞质，在细胞质中表达病毒蛋白并将基因组RNA传递至正在组装的病毒粒子。RRE组装形成一个Rev寡聚体，该寡聚体展示出核输出序列（NESs），以供Crm1-Ran（GTP）核受体复合物识别。在此，我们利用单颗粒电子显微镜首次呈现了组装好的HIV-宿主核输出复合物的结构。出乎意料的是，Crm1形成了一个具有广泛界面的二聚体，该界面增强了与Rev-RRE的结合，并使NES结合位点做好与Rev寡聚体相互作用的准备。Crm1单体之间的界面解释了不同Crm1直系同源物之间的差异，这些差异会改变核输出并决定病毒复制的细胞嗜性。输出复合物的排列确定了一个可能用于靶向HIV抑制剂的新结合表面，并且可能表明Crm1二聚化在调节宿主基因表达方面具有更广泛的作用。
