Structural and biochemical insights into multiple functions of HSV-1 UL21 in viral life cycle

HSV-1 UL21 在病毒生命周期中多种功能的结构和生化见解

基本信息

批准号：
8908572
负责人：
Claire Metrick
金额：
$ 3.89万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908572
关键词：
Affinity Bacterial RNA Binding Biochemical Biological Assay Biological Process Blindness C-terminal Capsid Cell Nucleus Cells Collaborations Communities Complex Cytoplasm DNA Data Disease Dissection Encephalitis Escherichia coli Future Gene Expression Genetic Transcription Genital system Genome Genomics Goals Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Infection Knowledge Length Life Life Cycle Stages Lipids Membrane Membrane Proteins Messenger RNA Methods Minor Modeling Molecular Models Mutagenesis N-terminal Nuclear Nuclear Envelope Nucleic Acid Binding Nucleic Acids Oral Pathway interactions Play Proteins Proteolysis Research Research Personnel Role Simplexvirus Structure System Testing Therapeutic Transcriptional Regulation United States Universities Vaccines Vesicle Viral Viral Genes Viral Proteins Virus Virus Replication Work base design in vitro activity insight latent infection molecular modeling novel novel therapeutics pathogen prevent protein complex protein function public health relevance skin lesion virus envelope

项目摘要

DESCRIPTION (provided by applicant): Herpes Simplex Viruses Type 1 and 2 (HSV-1 and HSV-2) are extremely prevalent and infect most people in the United States. These viruses cause lifelong, latent infections and can cause diseases from minor skin lesions to encephalitis. Unfortunately, preventative and therapeutic treatment options are limited. Networks of tegument proteins between the HSV-1 genomic capsid and envelope are likely to regulate many steps of the infection mechanism. A major gap in the progression of herpesvirology is the fact that the multiple specific functions of tegument proteins are largely unknown. Characterizing the many functions of these proteins is crucial to a complete understanding of the viral lifecycle. This proposal focuses on capsid-associated tegument protein UL21 that acts in the cytoplasm to regulate budding but is also found in the nucleus during infection. The objective of this proposal is to identify the multiple functions of HSV-1 UL21. The central hypothesis of this proposal is that UL21 has novel and unexplored nuclear functions in HSV-1 related to its ability to bind nucleic acids and localize to the nuclear rim. The hypothesis will be examined in two Specific Aims: Aim 1 will assess the binding of UL21 to nucleic acids and membranes to describe the mechanisms by which UL21 may regulate gene expression and nuclear egress, respectively. Furthermore, direct transcriptional effects of UL21 on UL16, another viral tegument protein, will be assayed in E coli. In Aim 2, the crystal structure of UL21 and its C- terminal domain will be solved and inspected for potential functional regions by characterizing the protein surface and by searching for structural similarity in proteins of known function. This proposal is significant because it will elucidate important functions previously hidden in the poorly understood tegument layer and aid researchers in assembling a more complete model of the infection mechanism-a necessary step to design new therapeutic strategies.

描述（由适用提供）：单纯疱疹病毒1型和2型（HSV-1和HSV-2）非常普遍，并且在美国被感染了大多数人。这些病毒会引起终生感染，并可能引起轻微皮肤病变的疾病到脑炎。不幸的是，预防性和治疗治疗方案受到限制。 HSV-1基因组上皮和包膜之间的Tegument蛋白网络可能调节感染机制的许多步骤。疱疹病毒学进展的一个主要差距是，Tegument蛋白的多个特定功能在很大程度上是未知的。表征这些蛋白质的许多功能对于完全了解病毒生命周期至关重要。该提案的重点是在细胞质中起作用的衣壳相关的Tegument蛋白UL21，以调节萌芽，但在感染过程中也发现了细胞核。该提案的目的是确定HSV-1 UL21的多个功能。该提案的中心假设是，UL21在HSV-1中具有与核酸结合并与核边缘定位的能力相关的新颖且意外的核功能。该假设将以两个具体的目的进行检查：AIM 1将评估UL21与核酸的结合和机制，以描述UL21可以调节基因表达和核出口的机制。此外，将在E大肠杆菌中分配UL21对另一种病毒tegument蛋白UL16的直接转录效应。在AIM 2中，将通过表征蛋白质表面并在已知功能的蛋白质中寻找结构相似性来解决UL21及其C末端结构域的晶体结构。该提案很重要，因为它将阐明以前隐藏在知识熟悉的团队层中的重要功能，并帮助研究人员组装了更完整的感染机制模型，这是设计新的治疗策略的必要步骤。