How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4.
How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4.
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作者：
Ren X;Park SY;Bonifacino JS;Hurley JH
HIV-1的Nef蛋白通过劫持网格蛋白接头复合物AP-2下调细胞表面共受体CD 4。Nef劫持AP-2的结构基础是通过与AP-2的α和σ2亚基结合的Nef的2.9 μ m晶体结构揭示的。Nef通过其中心环（残基149-179）和其核心与AP-2结合。Nef结合的决定因素包括直接接触AP-2的残基和稳定中心环的结合能力构象的其他残基。Nef与AP-2的结合和CD 4的下调都需要直接和间接相互作用中涉及的残基。这些结果导致了一个模型的对接的完整AP-2四聚体的膜结合Nef，这样的CD 4的胞质尾部位于与其结合位点的Nef相互作用。DOI：http://dx.doi.org/10.7554/eLife.01754.001病原体（如细菌或病毒）的感染激活了先天免疫反应（立即但不特异于病原体）和适应性免疫反应（更强且特异于病原体）.被称为CD 4 + T辅助细胞的白色血细胞在适应性免疫反应的早期阶段起着重要作用，它帮助激活和调节其他白色血细胞，进而消灭病原体。HIV-1是一种逆转录病毒，感染表面具有CD 4受体的免疫细胞，包括CD 4 + T辅助细胞。随着工作者CD 4 + T辅助细胞福尔斯数量的下降，适应性免疫应答逐渐减弱，HIV-1感染个体变得越来越容易感染和患病。当一个人的CD 4 + T辅助细胞计数福尔斯低于每微升200个细胞或他们开始经历与HIV-1感染相关的特定疾病时，就说他患上了艾滋病。为了预防和治疗艾滋病，研究人员致力于了解HIV-1基因组，并开发了针对参与病毒复制的病毒蛋白酶活性的药物。当这些药物联合使用时，有助于减少HIV-1的传播，并减少该疾病的死亡。然而，对副作用和耐药性的担忧意味着需要开发新药。HIV-1基因组编码许多辅助蛋白，包括一种称为Nef的蛋白质，它攻击CD 4 + T辅助细胞，去除赋予细胞名称的CD 4蛋白。这降低了T细胞激活免疫系统的能力，并允许病毒传播。Nef通过与T细胞中称为AP-2的蛋白质形成复合物来发挥作用，然后该复合物与CD 4蛋白质相互作用，导致它们被内化，然后在细胞内被破坏。Ren等人现在已经在分子水平上确定了Nef：AP-2复合物的结构，并鉴定了Nef蛋白中与AP-2蛋白相互作用的氨基酸残基。这使得Ren等人提出了复合物与CD 4蛋白之间相互作用的详细模型，以及这如何导致蛋白质被破坏。这些信息可用于开发药物，通过阻断AP-2上与Nef结合的氨基残基来发挥作用。此外，由于这些位点不易发生快速突变，因此此类药物不太可能遇到耐药性问题。DOI：http://dx.doi.org/10.7554/eLife.01754.002网站
The Nef protein of HIV-1 downregulates the cell surface co-receptor CD4 by hijacking the clathrin adaptor complex AP-2. The structural basis for the hijacking of AP-2 by Nef is revealed by a 2.9 Å crystal structure of Nef bound to the α and σ2 subunits of AP-2. Nef binds to AP-2 via its central loop (residues 149–179) and its core. The determinants for Nef binding include residues that directly contact AP-2 and others that stabilize the binding-competent conformation of the central loop. Residues involved in both direct and indirect interactions are required for the binding of Nef to AP-2 and for downregulation of CD4. These results lead to a model for the docking of the full AP-2 tetramer to membranes as bound to Nef, such that the cytosolic tail of CD4 is situated to interact with its binding site on Nef. DOI: http://dx.doi.org/10.7554/eLife.01754.001 Infection by a pathogen, such as a bacterium or virus, activates both the innate immune response—which is immediate but not specific to the pathogen—and the adaptive immune response, which is stronger and specific to the pathogen. White blood cells called CD4+ T helper cells play an important role in the early stages of the adaptive immune response by helping to activate and regulate other white blood cells that go on to eradicate the pathogen. HIV-1 is a retrovirus that infects immune cells that have the CD4 receptor on their surface, including CD4+ T helper cells. As the number of worker CD4+ T helper cells falls, the adaptive immune response gradually weakens, and the HIV-1 infected individual becomes increasingly susceptible to infection and disease. An individual is said to develop AIDS when either their CD4+ T helper cell count falls below 200 cells per microliter or they begin to experience specific diseases associated with the HIV-1 infection. In an effort to prevent and treat AIDS, researchers have worked to understand the HIV-1 genome and have developed medicines that target the enzymatic activity of viral proteins involved in viral replication. When used in combination, these drugs have helped to reduce transmission of HIV-1, and also to reduce deaths from the disease. However, worries about side effects and drug resistance mean that there is a need to develop new drugs. The HIV-1 genome codes for a number of accessory proteins, including a protein known as Nef that attacks the CD4+ T helper cells, removing the CD4 protein that gives the cells their name. This reduces the ability of the T cells to activate the immune system and allows the virus to spread. Nef acts by forming a complex with a protein called AP-2 in the T cells, and this complex then interacts with the CD4 proteins, causing them to be internalized and then destroyed inside the cells. Ren et al. have now worked out the structure of the Nef:AP-2 complex at the molecular level and identified the amino acid residues within the Nef protein that interact with the AP-2 protein. This allowed Ren et al. to propose a detailed model of the interaction between the complex and the CD4 protein, and how this leads to the protein being destroyed. This information could be used to develop drugs that work by blocking the amino residues on AP-2 that bind to Nef. Moreover, since these sites are not susceptible to rapid mutations, such drugs are less likely to encounter the problem of drug resistance. DOI: http://dx.doi.org/10.7554/eLife.01754.002