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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：
10113510
负责人：
Inna Afasizheva
金额：
$ 54.66万
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/10113510
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 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.

摘要