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

• 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
• 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

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.

项目摘要 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）cytidine家族 脱氨酶脱氨酸仅在脊椎动物中发现，所有APOBEC3亚家族蛋白都是 仅在灵长类动物中找到。通过脱氨基胞苷使DNA/RNA上的尿苷突变， APOBEC酶通过特定靶向对 意图的ssDNA或RNA通过包括空间和时间和时间的组合组合 底物特异性。例如，apobec1（a1）特异性地构成了蛋白质的mRNA 在胆汁淤积的代谢中发挥作用； APOBEC家族的另一个成员AID是需要的 抗体成熟过程，包括躯体超成熟和重组类开关； APOBEC2（A2）参与心脏和骨骼肌发育；和A3蛋白，一个 亚家族包含七个成员（AA-H），可以限制外国和内核酸，这些成员和内部核酸 对基因组完整性构成危险，其中包括内部恢复元件和转座作为 以及外部逆转录病毒和其他感染性病毒病原体，例如人类 免疫缺陷病毒（HIV），乙型肝炎病毒（HBV）。对于像HIV病毒这样的逆转录病毒 克服apobec enyzmes的抗HIV活性，它们编码一种称为VIF的蛋白质（病毒 毒性因子）特异性结合并通过无QUITINATION与APOBEC酶灭活 降级parthway。即使他们的脱氨活动是练习他们的关键 生物学功能，APOBEC酶在不适当的法规时可能意外突变 到位，这可能导致人类脱发，例如免疫艰难和癌症。我们的长期 术语目标是了解APOBEC蜂窝功能的结构/功能关系 及其抗病毒活性。我们的具体目的是了解Apobec的结构基础 功能以及基于底物特异性和抗HIV和抗病毒的机制 活动特别关注的是具有强大抗抗的APOBEC3亚家族成员 追溯和反HIV活动。这项拟议研究的结果将提供宝贵的 了解APOBEC酶家族和该分子细节的信息 底物特异性的机制，可用于潜在的药物开发 为艾滋病毒/艾滋病，免疫疾病和其他疾病（例如癌症）提供治疗。