Structure and activity of a cellular IRES element

细胞 IRES 元件的结构和活性

• 批准号: 7113590
• 负责人: Andrew Mehle
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2009-04-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113590
• 关键词: X ray crystallography; angiogenesis factor; bioimaging /biomedical imaging; genetic translation; messenger RNA; molecular /cellular imaging; nucleic acid structure; postdoctoral investigator; ribosomal proteins; ribosomes; structural biology; transcription factor; translation factor

DESCRIPTION (provided by applicant): Translation of mRNA is tightly regulated, requiring the ordered assembly of initiation factors and ribosomal subunits. Certain viral and cellular mRNAs circumvent traditional requirements for translation initiation by utilizing structured RNA elements termed internal ribosome entry sites (IRESs) to direct ribosomes to the translational start site. IRES structure is intimately linked to function, but the three-dimensional organization of cellular IRESs is poorly understood. This proposal aims to obtain a crystallographic structure of the IRES element in Cyr61 mRNA in complex with proteins required for its function, providing the first high-resolution structure of a cellular IRES element. Cyr61 is an angiogenic inducer suggested to play a critical role in tumor progression. Dicistronic reporter assays will define a minimal functional IRES and trans-acting factors required for activity will be identified. Chemical and enzymatic probing will determine the secondary structure of the Cyr61 IRES and identify structural elements amenable to crystallization. Results from this work will yield a detailed mechanistic understanding of the Cyr61 IRES and may elucidate mechanisms of cellular IRES activity, possibly identifying strategies to therapeutically manipulate Cyr61 production.

描述（由申请人提供）：mRNA的翻译受到严格的调节，需要有序的起始因子和核糖体亚基。某些病毒和细胞mRNA通过使用称为内部核糖体进入位点（IRESS）的结构化RNA元素来规避传统要求，以将核糖体直接直接核糖体。 IRES的结构与功能密切相关，但是三维细胞IRESS的组织知之甚少。该建议旨在获得与其功能所需的蛋白质复合物中IRES元件的晶体学结构，从而提供了细胞IRES元素的第一个高分辨率结构。 CYR61是一种血管生成诱导剂，建议在肿瘤进展中起关键作用。 DICISTROC RETORTORS分析将确定最小功能性IRE和活动所需的跨性别因素。化学和酶促探测将确定CYR61 IRES的二级结构，并确定可弥补的结构元素。这项工作的结果将对CYR61 IRES产生详细的机械理解，并可能阐明细胞IRES活性的机制，从而确定治疗方法操纵CYR61产生的策略。