Dehydroamino acids in HIV-1 capsid and matrix proteins: new potential targets for viral inactivation

HIV-1衣壳和基质蛋白中的脱氢氨基酸：病毒灭活的新潜在靶点

基本信息

批准号：
10762067
负责人：
LLOYD M SMITH
金额：
$ 18.77万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762067
关键词：
3-Dimensional Acids Acquired Immunodeficiency Syndrome Amino Acids Anti-Retroviral Agents Biological Biological Assay Biology Capsid Cells Chemicals Child Complex Cysteine Data Development Enzymes Glutathione HIV HIV Infections HIV-1 HIV-1 protease High Prevalence Histidine Human Hydrogenation Individual Knowledge Life Cycle Stages Literature Lyase Lysine Mass Spectrum Analysis Measures Modeling Modification Molecular Conformation Mutagenesis Mutate Mutation Output Pathway interactions Peptides Persons Play Post-Translational Protein Processing Process Production Property Proteins Proteome Proteomics Reaction Research Role Sampling Serine Site Site-Directed Mutagenesis Small Interfering RNA Structural Protein Suppressor Mutations Testing Therapeutic Threonine Viral Viral Proteins Virion Virus Virus Diseases Virus Inactivation Virus Replication Work candidate identification crosslink cycloaddition dehydroalanine dehydrobutyrine fascinate in vitro activity in vivo innovation insight knock-down matrix protein, Human immunodeficiency virus type 1 novel therapeutics overexpression pi bond protein crosslink screening transcriptomics

项目摘要

Project Summary/Abstract We have recently discovered dehydroamino acids (DHAAs) in the capsid and matrix proteins that make up HIV-1 virions. These dehydroalanine (DHA) and dehydrobutyrine (DHB) residues result from posttranslational modification of serine, threonine, or cysteine residues. We propose here to investigate the importance and origin of these fascinating protein modifications. Their high prevalence in these viral proteins, in marked contrast to their low levels in the human proteome generally, raises two key questions: a) why are they there? and b) how did they get there? We hypothesize that DHAAs are present in virions because they play important roles in the HIV virion assembly or capsid maturation. We hypothesize further that DHAAs are formed by a presently unknown enzymatic activity in viral or host proteins. To test these hypotheses, we will conduct mutation and inactivation studies of the amino acids that convert to dehydroamino acids and study the effects on the viral replication cycle and infectivity. We will use quantitative proteomics to determine how much of this modification is generated and whether it is before or after viral maturation. We will seek to discover intra- or intermolecular protein crosslinks, which dehydroamino acids are known to be able to form, using innovative proteomics approaches. Further, we will seek to discover the enzyme responsible for the formation of these modifications. The discovery of the enzyme responsible for DHAA formation would be interesting as fundamental biology, offer new insights into HIV replication, and potentially reveal a new therapeutic pathway for the treatment of HIV infection.

项目摘要/摘要我们最近发现了组成的衣壳和基质蛋白中的脱氢氨基酸（DHAA） HIV-1病毒体。这些脱氢丙氨酸（DHA）和脱氢布丁（DHB）残基是由翻译后引起的修饰丝氨酸，苏氨酸或半胱氨酸残基。我们在这里建议调查重要性和这些迷人的蛋白质修饰的起源。它们在这些病毒蛋白中的高患病率在标记中与他们在人类蛋白质组中的低水平形成鲜明对比，提出了两个关键问题：a）为什么它们在那里？ b）他们是如何到达那里的？我们假设Dhaas存在于病毒体中，因为它们发挥很重要在HIV病毒体组件或衣壳成熟中的作用。我们进一步假设DHAA是由目前在病毒或宿主蛋白中未知的酶活性。为了检验这些假设，我们将对转化为转换的氨基酸进行突变和灭活研究脱氢氨基酸并研究对病毒复制周期和感染性的影响。我们将使用定量蛋白质组学确定产生了多少这种修饰，是在病毒之前还是之后成熟。我们将寻求发现分子内或分子间蛋白交联，脱氢氨酸是已知能够使用创新的蛋白质组学方法形成。此外，我们将寻求发现负责形成这些修饰的酶。发现负责的酶 DHAA形成将作为基本生物学而有趣，提供有关艾滋病毒复制的新见解，并且潜在地揭示了一种用于治疗HIV感染的新治疗途径。