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Structure and function of Borna disease virus polymerase

博尔纳病病毒聚合酶的结构和功能

基本信息

批准号：
10656952
负责人：
Tomoaki Ogino
金额：
$ 24.87万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656952
关键词：
Amino Acids Animals Baculovirus Expression System Biochemical Biochemical Reaction Bioinformatics Biological Assay Biology Borna Disease Borna virus C-terminal Cell Nucleus Cells Complex Cryoelectron Microscopy Cytoplasm Ebola Elements Encephalitis Equus caballus Evolution Exhibits Filovirus Fossils Genetic Transcription Genome Glycine decarboxylase Goals Guanine Human In Vitro Insecta Interferons Messenger RNA Methylation Methyltransferase Molecular Mononegavirales Mutagenesis Nuclear Nuclear Proteins Paramyxovirus Play Pneumovirus Polymerase Production Proteins RNA Processing RNA Viruses RNA biosynthesis RNA chemical synthesis RNA-Directed RNA Polymerase Rabies Recombinants Reporting Rhabdoviridae Role Sheep Squirrel Structure System Testing Time Vertebrates Viral Viral Genome Virus Virus Replication Zoonoses cofactor human pathogen in vitro Assay innovation mRNA capping nervous system disorder novel protein complex prototype respiratory therapeutic target three dimensional structure tripolyphosphate viral RNA

项目摘要

Project Summary/Abstract Non-segmented negative strand (NNS) RNA viruses are highly diversified eukaryotic viruses including significant human pathogens (e.g., rabies, Nipah, Ebola). Most NNS RNA viruses replicate in the cytoplasm of host cells, whereas Borna disease virus 1 (BoDV-1), a unique NNS RNA virus, replicates in the nucleus. BoDV- 1 is a causative agent of fatal neurological diseases in animals and humans, although in rare cases. Interestingly, endogenous bornavirus-like elements were discovered as fossils of ancient bornaviruses in genomes of various vertebrates including humans, indicating that there have been interactions between bornaviruses and vertebrate hosts during evolution. Thus, elucidation of unique strategies of bornaviruses to replicate in host cells is important not only to understand the basic biology of bornaviruses but also to develop therapeutic targets against bornaviruses with zoonotic potential. The goal of this project is to elucidate the enzymatic roles of the RNA- dependent RNA polymerase (RdRp) complex composed of the BoDV-1 L and P proteins in transcription and replication. We hypothesize that (1) the BoDV-1 L protein has enzymatic activities to carry out genome transcription and replication and (2) the multimeric P protein plays structural roles in maintaining a transcriptionally active state of the L protein. These hypotheses will be tested by the specific aims to elucidate the roles of (1) the BoDV-1 L protein in RNA synthesis and processing and (2) the P protein in the formation of a transcriptionally active RdRp complex. In Aim 1, we will dissect the mechanisms underlying the formation of the unique termini of the genome and the 5′-terminal cap core structure on mRNAs with the BoDV-1 L-P complex. In Aim 2, we will solve a 3D structure of the BoDV-1 L-P complex and investigate the mechanism of the activation of the L protein with the multimeric P protein in RNA synthesis. Collectively, this study will advance our understanding of how the L protein of BoDV-1 carries out RNA synthesis and processing together with its co- factor P protein. Furthermore, this study will reveal structural similarities and differences between RdRp complexes of nuclear- and cytoplasmic- replicating NNS RNA viruses.

项目总结/文摘