Investigation of viral ribonucleic acid recognition by 2'-5'-oligoadenylate synthetases

许多病毒感染的标志是在病毒的生命周期期间产生外源核酸分子。宿主细胞通过多种机制对这些外来生物分子做出反应，包括使用核酸传感器蛋白来检测并建立针对感染的防御反应。McKenna实验室将重点研究一个非常重要的核酸结合蛋白家族，该家族对病毒感染的识别至关重要：2 '-5'寡腺苷酸合成酶（OAS）。OAS酶和外源核酸分子之间的相互作用有助于通过阻断必要的病毒蛋白质产生来防止病毒复制。我的实验室将建立一个研究计划，以表征自然发生的病毒核酸分子和OAS酶之间的相互作用，以提供对宿主细胞应对病毒入侵的关键机制的基本理解。生物物理表征将确定病毒核酸分子的关键特征，结构生物学方法将生成感兴趣的复合物的三维图像。拟议的研究计划的一个新方面是使用天然存在的病毒核酸分子作为模型系统;迄今为止，大多数研究都采用了缺乏病毒对应物典型关键特征的合成核酸分子。 因此，拟议研究计划的预期结果将有助于我们了解OAS酶如何区分病毒和宿主细胞核酸分子。麦肯纳实验室的学员已经并将继续受益于申请人在蛋白质-核酸相互作用研究方面的专业知识，并获得了一套有需求的技能，因为这些相互作用在各种生物学重要系统中具有重要意义。经过培训的高素质人员将为从事生物技术、分子生物学、生物化学、结构生物学和蛋白质组学等基础科研的职业做好充分准备。

A hallmark of many viral infections is the production of foreign nucleic acid molecules that are generated during the life cycle of the virus. Host cells respond to these foreign biomolecules through a variety of mechanisms, including the use of nucleic acid sensor proteins that detect and mount a defensive response against the infection. The McKenna laboratory will focus investigation on an extremely important family of nucleic-acid binding proteins that are central to the recognition of viral infection: 2'-5' oligoadenylate synthetases (OAS). The interaction between OAS enzymes and foreign nucleic acid molecules helps to prevent viral replication by blocking necessary viral protein production. My laboratory will establish a research program to characterize the interactions between naturally occurring viral nucleic acid molecules and OAS enzymes to provide a fundamental understanding of a key mechanism used by host cells to respond to viral invasion. Biophysical characterization will identify key features of viral nucleic acid molecules, and structural biology approaches will generate three-dimensional images of complexes of interest. A novel aspect of the proposed research program is the use of naturally occurring viral nucleic acid molecules as the model systems; most studies to date have employed synthetic nucleic acid molecules that lack key characteristics typical of their viral counterparts. The results expected from the proposed research program will therefore contribute to our understanding of how OAS enzymes distinguish between viral and host-cell nucleic acid molecules. Trainees in the McKenna laboratory have and will continue to benefit from the applicant's expertise in the investigation of protein-nucleic acid interactions and acquire an in-demand skill set given the emerging importance of these interactions in a wide variety of biologically important systems. Highly qualified personnel trained will be well equipped for careers in basic scientific research focused on biotechnology, molecular biology, biochemistry, structural biology, and proteomics.