Structural Basis of APOBEC Functions and Interactions with HIV-Vif

APOBEC 功能的结构基础以及与 HIV-Vif 的相互作用

基本信息

批准号：
9537133
负责人：
XIAOJIANG S CHEN
金额：
$ 4.52万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9537133
关键词：
AIDS/HIV problem APOBEC2 gene Acquired Immunodeficiency Syndrome Antibodies Binding Biochemical Biological Process Cell physiology Cholesterol Complementary DNA Complex Core-Binding Factor Crystallography Cullin 5 Protein Cytidine Cytidine Deaminase Cytosine deaminase DNA Deaminase Deamination Development Disease Enzymes Family Genetic Recombination Genome Stability Genomic Instability Goals HIV HIV Infections HIV therapy HIV-1 Hepatitis B Human Human Genome Hyperimmunoglobulin M Syndrome Immune Immune System Diseases Immunity Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Infection Knowledge Lead Length Malignant Neoplasms Mediating Messenger RNA Metabolism Methods Molecular Molecular Target Muscle Development Mutate Mutation Myocardium Natural Immunity Nucleic Acid Binding Nucleic Acids Outcome Play Primates Process Property Proteins RNA RNA Binding Reagent Recruitment Activity Regulation Research Resolution Retroelements Retrotransposition Retroviridae Risk Role Sequence Homology Skeletal Muscle Specificity Structure Substrate Interaction Substrate Specificity Thinness Uridine Vertebrates Viral Viral Physiology Virion Virulent Virus acquired immunity apoB mRNA editing catalytic subunit drug development effective therapy elongin B fight against genome integrity member novel novel strategies pathogen polypeptide prevent single molecule ubiquitin-protein ligase

项目摘要

Project Summary Structural Basis of APOBEC Functions and Interactions with HIV-Vif The APOBEC (Apolioprotein B mRNA-editing Enzyme Catalytic polypeptide) family of cytidine deaminases deaminate are found only in vertebrates and all APOBEC3 subfamily proteins are found only in primates. By deaminating the cytidine to cause mutation to uridine on DNA/RNA, APOBEC enzymes achieve remarkably diverse cellular functions through specific targeting to the intented ssDNA or RNA through a combination of regulations including spatial and temporal and substrate specificity. For example, APOBEC1 (A1) specifically modigy the mRNA of a protein that play a role in cholestoral metabolism; AID, another member of APOBEC family, is required for antibody maturation process including somatic hypermutation and recombination class switch; APOBEC2 (A2) is involved in cardiac and skeletal muscle development; and A3 proteins, a subfamily contains seven members (AA-H), can restrict foreign and internal nucleic acids that poses danger to the genome integrity, which include internal retroelements and transposons as well as external retroviruses and otherinfectious viral pathogens, such as Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) . For retroviruses like HIV viruses to overcome the anti-HIV activity of APOBEC enyzmes, they encode a protein called Vif (virus virulent factor) that specifically bind to and inactivate APOBEC enzymes through unbuquitination degradation parthway. Even though their deamination activity is the key to excercute their biological functions, APOBEC enzymes can accidental mutations when proper regulations are not in place, which could lead to human deseases such as immune difficiency and cancer. Our long- term goals are to understand the structural/functional relationship for APOBEC cellular function and their anti-viral activity. Our specific aims are to understand the structural basis of APOBEC's functions and and the mechanisms that underlie substrate specificity and anti-HIV and anti-viral activities, with particular focuses on the APOBEC3 subfamily members that have strong anti- retroelements and anti-HIV activities. The outcome of this proposed research will provide valuable information for understanding the molecular details of the APOBEC enzyme family and the mechanisms of substrate specificity, which can be used for the potential drug development to provide therapy for HIV/AIDS, immune disorders, and other diseases such as cancer.

项目概要 APOBEC 功能的结构基础以及与 HIV-Vif 的相互作用 APOBEC（载脂蛋白 B mRNA 编辑酶催化多肽）胞苷家族脱氨酶脱氨仅存在于脊椎动物中，并且所有 APOBEC3 亚家族蛋白都是仅在灵长类动物中发现。通过胞苷脱氨基导致 DNA/RNA 上的尿苷突变， APOBEC 酶通过特异性靶向通过空间和时间等法规的组合来实现有意的 ssDNA 或 RNA 底物特异性。例如，APOBEC1 (A1) 特异性修饰蛋白质的 mRNA，该蛋白质在胆甾醇代谢中发挥作用； AID 是 APOBEC 家族的另一个成员，需要抗体成熟过程包括体细胞超突变和重组类别转换； APOBEC2 (A2) 参与心肌和骨骼肌的发育；和 A3 蛋白，亚家族包含七个成员（AA-H），可以限制外来和内部核酸对基因组完整性构成危险，其中包括内部逆转录元件和转座子以及外部逆转录病毒和其他传染性病毒病原体，例如人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）。对于 HIV 病毒等逆转录病毒克服 APOBEC 酶的抗 HIV 活性，它们编码一种称为 Vif（病毒毒力因子），通过去丁蛋白化特异性结合 APOBEC 酶并使其失活降解途径。尽管他们的脱氨基活动是发挥其作用的关键 APOBEC 酶的生物学功能在没有适当监管的情况下可能会发生意外突变到位，这可能会导致人类疾病，例如免疫缺陷和癌症。我们的长期术语目标是了解 APOBEC 细胞功能的结构/功能关系及其抗病毒活性。我们的具体目标是了解 APOBEC 的结构基础底物特异性和抗 HIV 和抗病毒的功能和机制活动，特别关注具有强抗- 逆转录因子和抗 HIV 活性。这项拟议研究的结果将提供有价值的用于了解 APOBEC 酶家族的分子细节和底物特异性机制，可用于潜在的药物开发提供艾滋病毒/艾滋病、免疫紊乱和癌症等其他疾病的治疗。