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A novel preribosomal complex in trypanosomes

锥虫中的一种新型前核糖体复合物

基本信息

批准号：
8448653
负责人：
Noreen Williams
金额：
$ 35.74万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448653
关键词：
African Trypanosomiasis Antibiotics Bacteria Binding Binding Proteins Biogenesis Biological Assay Cell Nucleolus Cell Nucleus Chagas Disease Chemicals Complex Computer Simulation Data Databases Disease Drug Targeting Energy Transfer Fluorescence Gel Goals Homologous Gene Human Immune In Vitro Intervention Ketolides Leishmania Leishmaniasis Macrolides Maintenance Maps Mediating Methods Molecular Mutation Nucleoplasm Organism Parasites Pathway interactions Play Process Protein Binding Domain Protein Fragment Proteins RNA-Binding Proteins Research Resolution Ribosomal Biogenesis Pathway Ribosomal RNA Role Route Signal Transduction Small RNA Staging Structure System Technology Testing Transcription Factor TFIIIA Trypanosoma Trypanosoma brucei brucei Trypanosoma cruzi Work base chemotherapy domain mapping in vivo migration novel particle public health relevance research study ribosomal protein L5 screening trafficking

项目摘要

DESCRIPTION (provided by applicant): We have shown that two trypanosome-specific RNA binding proteins, P34 and P37, play an essential role in the ribosomal biogenesis pathway in T. brucei. This represents a novel finding since the ribosomal pathway is highly conserved. To exploit this observation for the ultimate goal of targeting the T. brucei ribosomal pathway in chemotherapy, we must understand the mechanism by which these proteins act in the pathway. In recent work, we have shown that P34 and P37 interact with both L5 and 5S rRNA, the highly conserved components of the preribosomal particle. Loss of P34/P37 leads to a decrease in 5S rRNA levels and other effects in ribosomal formation. The objective of this proposal is to determine the critical residues involved in this interaction and develop a method to identify molecules that disrupt this interaction. Our hypothesis is that the molecular interactions of these proteins will provide a valid target for intervention in ribosomal assembly in T. brucei. The specific aims of the project are to: 1. Determine the critical molecular determinants on L5 and P34/P37 that are required for participation in the T. brucei preribosomal complex. 2. Determine the critical regions on 5S rRNA that interact with L5 and P34/P37 in the T. brucei preribosomal complex. 3. Determine whether the interaction of P34/P37 with L5 and 5S rRNA is required for trafficking of the complex to the nucleolus. 4. Develop a FRET (fluorescence energy transfer) based screen for the disruption of the interaction between P34/P37, L5, and 5S rRNA in the preribosomal particle. Differences in ribosomal structure and function between bacteria and the infected human host have provided targets for macrolide and ketolide antibiotics. Since this preribosomal particle is unique to kinetoplastids and play an essential role in the ribosomal structure and biogenesis in these organisms, mechanistic studies with this complex will allow us to define a strategic target for chemical intervention.

描述（由申请人提供）：我们已经证明两种锥虫特异性RNA结合蛋白P34和P37在锥虫核糖体生物合成途径中起重要作用。布鲁塞。这是一个新的发现，因为核糖体途径是高度保守的。为了利用这一观察结果，最终目标是瞄准T。为了研究布鲁氏菌核糖体途径在化疗中的作用，我们必须了解这些蛋白在该途径中的作用机制。在最近的工作中，我们已经表明，P34和P37与L5和5S rRNA，前核糖体颗粒的高度保守的成分相互作用。P34/P37的缺失导致5S rRNA水平的降低和核糖体形成中的其他效应。该提案的目的是确定参与这种相互作用的关键残基，并开发一种方法来识别破坏这种相互作用的分子。我们的假设是，这些蛋白质的分子相互作用将提供一个有效的目标，在核糖体组装的干预在T。布鲁塞。该项目的具体目标是：1.确定参与T所需的L5和P34/P37上的关键分子决定因素。布氏杆菌前核糖体复合物。2.确定T细胞中与L5和P34/P37相互作用的5S rRNA关键区域。布氏杆菌前核糖体复合物。3.确定P34/P37与L5和5S rRNA的相互作用是否是将复合物运输到核仁所必需的。4.开发基于FRET（荧光能量转移）的筛选，以破坏前核糖体颗粒中P34/P37、L5和5S rRNA之间的相互作用。细菌和感染的人类宿主之间核糖体结构和功能的差异为大环内酯类和酮内酯类抗生素提供了靶点。由于这种前核糖体颗粒是动质体所特有的，并在这些生物体的核糖体结构和生物发生中发挥重要作用，因此对这种复合物的机制研究将使我们能够确定化学干预的战略目标。