Structural Basis of APOBEC Functions and HIV Restriction

APOBEC 功能和 HIV 限制的结构基础

• 批准号: 10013651
• 负责人: XIAOJIANG S CHEN
• 金额: $ 44.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10013651
• 关键词: 3-Dimensional; AIDS/HIV problem; APOBEC2 gene; Address; Affinity; Anti-HIV Agents; Antibodies; Antiviral Agents; Binding; Biological; Biological Process; Biology; C-terminal; Cardiac; Cell physiology; Cholesterol; Cholesterol Homeostasis; Complementary DNA; Complex; Cryoelectron Microscopy; Cullin 5 Protein; Cytidine; Cytidine Deaminase; Cytosine deaminase; DNA; DNA Viruses; Deaminase; Deamination; Disease; Enzymes; Factor V; Family; Generations; Genome Stability; Genomic Instability; Genomics; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Hepatitis B Virus; Human; Human Genome; Human Papillomavirus; Hyperimmunoglobulin M Syndrome; Immune; Immune System Diseases; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Infection; Lead; Length; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Muscle Development; Mutation; Myocardium; N-terminal; Natural Immunity; Nucleic Acids; Outcomes Research; Play; Proteins; RNA; RNA Binding; RNA Viruses; RNA-Directed DNA Polymerase; Regulation; Retroelements; Retrotransposition; Retroviridae; Reverse Transcription; Risk; Roentgen Rays; Role; Skeletal Muscle; Specificity; Structure; Substrate Specificity; Ubiquitination; Uridine; Viral; Viral Physiology; Virion; Virulent; Virus; Virus Diseases; Virus Replication; antiviral immunity; apoB mRNA editing catalytic subunit; apolipoprotein B mRNA editing enzyme; cofactor; drug development; effective therapy; elongin B; genome integrity; human disease; member; multicatalytic endopeptidase complex; novel; pathogenic virus; polypeptide; prevent; recruit; ubiquitin-protein ligase; viral genomics

Project Summary Structural Basis of APOBEC Functions and HIV Restriction Apolipoprotein B mRNA-editing Enzyme Catalytic polypeptide (APOBEC) family of cytidine deaminases are capable of deaminating the cytidine to cause mutation to uridine on DNA or RNA. Human APOBEC deaminases have remarkable diverse cellular functions through specific targeting to the intended ssDNA or RNA through a combination of regulations including spatial and temporal distribution and substrate specificity. For example, APOBEC1 (A1) edits certain RNAs with the help of specific cofactors to regulate cholesterol metabolism; AID has important role in acquired immune response, it is required for antibody maturation including somatic hypermutation (SHM) and class switch recombination (CSR); APOBEC2 (A2) is involved in cardiac and skeletal muscle development; and APOBEC3 proteins (A3s, A3A-H) plays an important role in innate immunity for anti-viral activity, they can restrict internal and external nucleic acids (such as RNA and DNA viruses and retroelements) that poses danger to the genome integrity, which include internal retroelements as well as external retroviruses and other infectious viral pathogens, such as Hepatitis B Virus (HBV), Human Papillomavirus (HPV), and Human Immunodeficiency Virus (HIV). Among APOBEC proteins, A3G/A3F/A3D/A3H display strong anti-HIV activity, which are through deaminase-dependent and -independent mechanisms to inhibit viral replication and infection. However, retroviruses like HIV-1 can overcome the anti-HIV activity of APOBEC enzymes by its virus virulent factor (Vif) that specifically recruit cellular Cul5 E3 ligase to target these APOBECs for ubiquitination and degradation, leading to the viral infection. The deamination activity of APOBECs can also cause accidental genomic mutations, which can lead to various human diseases such as immune deficiency and cancer. Our long-term scientific goals are to understand the structural/functional relationship for APOBEC cellular functions and their anti-viral activities. Our specific aims are to understand the structural basis of APOBEC’s functions and the mechanisms that underlie nucleic acid interactions, multimerization, functional regulation, and viral restriction, with particular focuses on the double domain APOBEC3 subfamily members that have strong anti-retroelements and anti-HIV activities. The outcome of this research will provide valuable information for the fundamental molecular mechanisms of APOBEC functions and their anti viral activities, which can be used for the potential drug development to provide therapy for HIV/AIDS, immune disorders, and other diseases such as cancer.

项目摘要 APOBEC功能和HIV限制的结构基础 载脂蛋白B mRNA编辑酶催化多肽（APOBEC）胞苷家族 脱氨酶能够使胞苷脱氨酶在DNA或RNA上导致尿苷突变。 人apobec脱氨酶通过特定的靶向具有显着的大型细胞功能 通过包括空间和临时的法规组合到预期的ssDNA或RNA 分布和底物特异性。例如，apobec1（a1）在帮助的情况下编辑某些RNA 特定的辅助因子来调节胆固醇代谢；援助在获得免疫中起重要作用 响应，这是抗体成熟所必需的，包括躯体超松（SHM）和类 开关重组（CSR）； APOBEC2（A2）参与心脏和骨骼肌肉 发展;和APOBEC3蛋白（A3S，A3A-H）在先天免疫中起重要作用 抗病毒活性，它们可以限制内部和外部核酸（例如RNA和DNA 病毒和逆向元素）对基因组完整性具有危险，其中包括内部 恢复元素以及外部逆转录病毒和其他感染性病毒病原体，例如 丙型肝炎病毒（HBV），人乳头瘤病毒（HPV）和人类免疫缺陷病毒（HIV）。 在APOBEC蛋白中，A3G/A3F/A3D/A3H表现出强大的抗HIV活性，这是通过 脱氨酶依赖性和非依赖性机制抑制病毒复制和感染。 但是，像HIV-1这样的逆转录病毒可以通过其酶来克服APOBEC酶的抗HIV活性 病毒病毒因子（VIF）专门募集细胞CUL5 E3连接酶以这些apobecs靶向 泛素化和降解，导致病毒感染。 apobecs的脱氨酸活动 也可能引起意外的基因组突变，这可能导致各种人类疾病，例如 免疫缺陷和癌症。 我们的长期科学目标是了解 APOBEC细胞功能及其抗病毒活性。我们的具体目的是了解 APOBEC功能的结构基础和基于核酸相互作用的机制， 多层次化，功能调节和病毒限制，特别关注双重 域APOBEC3亚家族成员具有强大的抗重新元素和抗HIV活性。 这项研究的结果将为基本分子提供有价值的信息 APOBEC功能的机制及其抗病毒活性，可用于潜力 为艾滋病毒/艾滋病，免疫疾病和其他疾病提供治疗的药物开发，例如 癌症。