REPEAT-CONTAINING RNA BINDING PROTEINS OF TRYPANOSOMES

锥虫的含有重复序列的 RNA 结合蛋白

基本信息

批准号：
10335277
负责人：
Inna Afasizheva
金额：
$ 48.43万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-05 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10335277
关键词：
5&apos Untranslated Regions Affinity African Animals Antigenic Variation Architecture Area Binding Binding Sites Biogenesis Biology Biotinylation Chemicals Complex Consensus Sequence Conserved Sequence Cryoelectron Microscopy Custom Diphosphates Disease Economic Burden Elements Ensure Enzymes Event Exposure to Family Funding Gene Expression Genetic Genetic Materials Genetic Transcription Genetic Translation Goals Guide RNA Health Hazards Helix-Turn-Helix Motifs Human Hydrolysis In Vitro Individual Knowledge Laboratories Mass Spectrum Analysis Mastigophora Mediating Medical Messenger RNA Mitochondria Mitochondrial RNA Modality Modeling Modification Molecular Monitor Mutate Mutation Nuclear Organelles Organism Outcome Parasites Parasitic infection Plants Poly(A)-Binding Proteins Polynucleotide Adenylyltransferase Positioning Attribute Post-Transcriptional Regulation Pre-mRNA Polyadenylation Factor Process Property Protein Biosynthesis Protein Engineering Proteins Public Health RNA RNA Binding RNA Degradation RNA Sequences RNA-Binding Proteins Reaction Reader Reading Resolution Resources Ribosomes Role Science Site Specificity Structure Substrate Specificity Tail Testing Therapeutic Transcript Transcription Initiation Translational Activation Translations Trypanosoma Trypanosoma brucei brucei Trypanosomiasis Vaccines Validation X-Ray Crystallography base crosslink endonuclease gene discovery health economics high reward high risk in vivo innovation insertion/deletion mutation knock-down mRNA Precursor mRNA Stability mRNA Surveillance mRNA Transcript Degradation marginalized population mitochondrial messenger RNA new therapeutic target novel pathogen polypeptide prevent programs promoter reconstitution recruit ribosome profiling sensor translational potential vector control

项目摘要

ABSTRACT Flagellated kinetoplastid protozoans inflict public health hazards and economic burden predominately on marginalized populations in the developing world. The agents of African human and animal trypanosomiasis, Trypanosoma brucei sp., cause some of the most-studied, but least manageable and curable parasitic infections. Failing vector control, lack of vaccines and toxic therapeutics place the onus on identification, molecular understanding and validation of new drug targets. From the fundamental science perspective, these early branching Excavata represent valuable models of mitochondrial RNA biology, antigenic variation, host-pathogen interaction, post-transcriptional regulation, and other processes. Major findings in the previous funding period position a family of RNA binding pentatricopeptide repeat (PPR, 35 amino acids) proteins as the central conduit controlling mitochondrial gene expression. The unique ability of helix-turn-helix repeats to assemble into superhelical arrays recognizing extended and compositionally diverse RNA sequences enables the essential roles of more than 40 PPRs. Often including trypanosome-specific domains, these RNA “sequence readers” commit otherwise non-specific modification enzymes to their substrates, or block RNA degradation and extension. This project will elucidate the mechanisms by which nuclear-encoded PPRs govern mitochondrial mRNA biogenesis and translation via recruiting enzymatic complexes and ribosomes to transcripts at defined processing stages. We establish three priority areas focusing on PPRs that enable mRNA 5′ end modification, 3′ adenylation/uridylation, and translation. Building on our recent discoveries of gene-specific transcription initiation and exonucleolytic pre-mRNA processing, we identified PPR factors acting as “protein cap,” “editing sensor,” poly(A) binding protein, and potential translational activators. Our goal is to dissect the molecular machinery integrating these functions and to decipher principles of RNA recognition by repeat-containing proteins. By elucidating their RNA binding sites, structures, interactions, and outcomes of genetic alteration and protein engineering, this program builds on our momentum in a significant field and expands the knowledge of critical pathogen-specific processes.

抽象的鞭打的动力质体原生动物造成了公共卫生危害，经济伯宁主要对发展中国家的边缘化人群。非洲人类和动物锥虫病的特工， Brucei Sp。锥虫引起的一些最受研究的感染，但最不可能且最不可能的感染。载体控制失败，缺乏疫苗和有毒疗法将责任放在鉴定上，分子了解和验证新药物靶标。从基本的科学角度来看，这些早期分支excavata代表了线粒体RNA生物学，抗原变异，宿主病原的有价值模型相互作用，转录后调节和其他过程。上一流的重大发现将RNA结合五肽重复（PPR，35个氨基酸）蛋白的家族定位为中央导管控制线粒体基因表达。螺旋 - 转动螺旋重复的独特能力，可以组装成识别扩展和合成多样的RNA序列的超螺旋阵列使必需 40多个PPR的角色。这些RNA通常包括特定于锥体特异性域，这些RNA“序列读取器” 将其他非特异性修饰酶提交给其底物，或阻止RNA降解和扩大。该项目将阐明核编码PPRS的机制 mRNA生物发生和通过募集酶复合物和核糖体转化为定义的转录本处理阶段。我们建立了三个优先领域，重点是启用mRNA 5'结束修改的PPR， 3'腺苷酸化/尿苷和翻译。建立在我们最近的基因特异性转录的基础上启动和外核解液中MRNA处理，我们确定了起作用的PPR因子，是“蛋白质帽”，“编辑” 传感器，“ poly（a）结合蛋白和潜在的翻译激活剂。我们的目标是剖析分子通过重复进行的机械集成了这些功能和破译RNA识别的原理蛋白质。通过阐明其RNA结合位点，结构，相互作用以及遗传改变和结果蛋白质工程，该程序以我们在一个重要领域的动力为基础，并扩展了知识关键的病原体特异性过程。