RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev-Rev response element complex.
RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev-Rev response element complex.
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DOI：
10.7554/elife.04120
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发表时间：
2014-12-08
期刊：
影响因子：
7.7
通讯作者：
Frankel AD
中科院分区：
文献类型：
--
作者：
Jayaraman B;Crosby DC;Homer C;Ribeiro I;Mavor D;Frankel AD
HIV-1蛋白Rev通过介导未剪接和单剪接病毒mRNAs的核输出，控制病毒复制的关键步骤。多个REV亚基聚集在REV反应元件(RRE)上，RRE是这些RNA中存在的一个结构化区域，并通过CRM1途径引导它们的输出。REV-RRE组装通过几个REV齐聚和RNA结合步骤进行，但这些步骤如何协调以形成具有出口能力的复合体尚不清楚。在这里，我们报道了REV二聚体-RRE复合体的第一个晶体结构，揭示了REV-二聚体在RRE结合时通过重新包装其疏水蛋白质-蛋白质界面而发生的戏剧性重排。REV-RNA识别依赖于特征良好的IIB位点的序列特异性接触和第二个位点的本地RNA结构。该结构支持一种模型，在该模型中，RRE利用REV亚单位界面的固有可塑性来指导功能复合体的形成。DOI：http://dx.doi.org/10.7554/eLife.04120.001为了能够繁殖，病毒必须首先感染宿主细胞，然后劫持宿主的分子机器来制造病毒蛋白质。这个过程的一个阶段发生在宿主细胞的细胞核中，涉及到转录病毒DNA来制造RNA分子。然后，这些RNA分子必须从细胞核输出到细胞质，在那里制造病毒蛋白。就HIV-1而言，一种名为REV的蛋白质在出口过程中发挥着重要作用。REV蛋白由病毒提供，与病毒RNA分子上称为REV反应元件的区域结合。然后，REV蛋白与一组称为CRM1出口复合体的宿主蛋白结合，将病毒RNA分子送到细胞质。Jayaraman等人。现在提供与REV响应元件的片段结合的两个REV分子的第一个深度3D结构。REV分子与元素结合时会改变形状，元素的特定区域被发现对此很重要。实验表明，REV反应元件指导REV蛋白在自身上的定位，以匹配与CRM1出口复合体结合所需的形状。在同一实验室的平行工作中，Booth等人。已经制作了整个建筑群的3D结构。这两个结构都为HIV-1病毒如何在宿主体内繁殖提供了新的线索，这可能有助于未来开发该疾病新疗法的努力。DOI：http://dx.doi.org/10.7554/eLife.04120.002
The HIV-1 protein Rev controls a critical step in viral replication by mediating the nuclear export of unspliced and singly-spliced viral mRNAs. Multiple Rev subunits assemble on the Rev Response Element (RRE), a structured region present in these RNAs, and direct their export through the Crm1 pathway. Rev-RRE assembly occurs via several Rev oligomerization and RNA-binding steps, but how these steps are coordinated to form an export–competent complex is unclear. Here, we report the first crystal structure of a Rev dimer-RRE complex, revealing a dramatic rearrangement of the Rev-dimer upon RRE binding through re-packing of its hydrophobic protein–protein interface. Rev-RNA recognition relies on sequence-specific contacts at the well-characterized IIB site and local RNA architecture at the second site. The structure supports a model in which the RRE utilizes the inherent plasticity of Rev subunit interfaces to guide the formation of a functional complex. DOI: http://dx.doi.org/10.7554/eLife.04120.001 To be able to multiply, viruses have to first infect a host cell and then hijack the host's molecular machinery to make viral proteins. One stage of this process takes place in the nucleus of the host cell and involves the viral DNA being transcribed to make RNA molecules. These RNA molecules must then be exported from the nucleus to the cytoplasm, where the viral proteins are made. In the case of HIV-1, a protein called Rev has an important role in the export process. The Rev protein, which is supplied by the virus, binds to a region on the viral RNA molecules called the Rev Response Element. The Rev protein then binds to a group of host proteins called the Crm1 export complex to send the viral RNA molecules to the cytoplasm. Jayaraman et al. now provide the first in-depth 3D structure of two Rev molecules bound to a fragment of the Rev Response Element. The Rev molecules change shape when they bind to the element, and specific regions of the element were found to be important for this. The experiments suggest that the Rev Response Element directs the positioning of the Rev proteins on itself to match the shape needed to bind to Crm1 export complex. In parallel work from the same laboratory, Booth et al. have produced a 3D structure of the whole complex. Both structures shed new light on how the HIV-1 virus is able to multiply in its host, which may aid future efforts to develop new treatments for the disease. DOI: http://dx.doi.org/10.7554/eLife.04120.002