Structural Basis of APOBEC Functions and HIV Restriction

APOBEC 功能和 HIV 限制的结构基础

• 批准号: 10436802
• 负责人: XIAOJIANG S CHEN
• 金额: $ 41.26万
• 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/10436802
• 关键词: 3-Dimensional; AIDS/HIV problem; APOBEC2 gene; Address; Affinity; Anti-HIV Agents; Antibodies; 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功能的结构基础与HIV限制 胞苷的载脂蛋白B mRNA编辑酶催化多肽（APOBEC）家族 脱氨酶能够使胞苷脱氨以引起DNA或RNA上尿苷的突变。 人APOBEC脱氨酶通过特异性靶向作用具有显著的多样性细胞功能 通过包括空间和时间调节的组合， 分布和底物特异性。例如，APOBEC 1（A1）在RNA的帮助下编辑某些RNA。 特异性辅因子调节胆固醇代谢; AID在获得性免疫中具有重要作用 在免疫应答中，它是抗体成熟所必需的，包括体细胞超突变（SHM）和类 开关重组（CSR）; APOBEC 2（A2）参与心肌和骨骼肌 APOBEC 3蛋白（A3 s，A3 A-H）在先天免疫中起着重要作用， 抗病毒活性，它们可以限制内部和外部核酸（如RNA和DNA 病毒和逆转录因子），对基因组的完整性构成威胁，包括内部 逆转录因子以及外部逆转录病毒和其他感染性病毒病原体，如 B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，A3 G/A3 F/A3 D/A3 H显示出强的抗HIV活性，其通过免疫印迹法（ELISA）检测。 脱氨酶依赖性和非依赖性机制抑制病毒复制和感染。 然而，逆转录病毒如HIV-1可以通过其自身的抗HIV活性来克服APOBEC酶的抗HIV活性。 病毒毒力因子（Vif）特异性募集细胞Cul 5 E3连接酶以靶向这些APOBEC， 泛素化和降解，导致病毒感染。APOBECs的脱氨活性 也可能导致意外的基因组突变，这可能导致各种人类疾病， 免疫缺陷和癌症。 我们的长期科学目标是了解结构/功能关系， APOBEC细胞功能及其抗病毒活性。我们的具体目标是了解 APOBEC功能的结构基础和核酸相互作用的机制， 多聚化，功能调节和病毒限制，特别关注双 结构域APOBEC 3亚家族成员，具有较强的抗逆转录因子和抗HIV活性。 本研究的结果将为基础分子生物学提供有价值的信息 APOBEC功能的机制及其抗病毒活性，可用于潜在的 药物开发，为艾滋病毒/艾滋病、免疫紊乱和其他疾病提供治疗， 癌