Structural Basis of APOBEC Functions and Interactions with HIV-Vif

项目摘要 APOBEC功能的结构基础及其与HIV-Vif的相互作用 胞苷的APOBEC（载脂蛋白B mRNA编辑酶催化多肽）家族 仅在脊椎动物中发现脱氨酶脱氨，并且所有APOBEC 3亚家族蛋白均 只在灵长类中发现通过胞苷脱氨基使DNA/RNA突变为尿苷， APOBEC酶通过特异性靶向细胞内的 通过包括空间和时间的调节的组合， 底物特异性例如，APOBEC 1（A1）特异性修饰一种蛋白质的mRNA， 在胆固醇代谢中起作用; AID是APOBEC家族的另一成员， 抗体成熟过程包括体细胞超突变和重组类转换; APOBEC 2（A2）参与心脏和骨骼肌发育; 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， 对基因组的完整性构成危险，包括内部逆转录因子和转座子， 以及外部逆转录病毒和其他感染性病毒病原体，如人 免疫缺陷病毒（HIV）、B肝炎病毒（HBV）。对于逆转录病毒，如艾滋病毒， 克服APOBEC酶的抗HIV活性，它们编码一种称为Vif（病毒）的蛋白质 毒力因子）特异性结合并通过去乙酰化作用抑制APOBEC酶 降解途径。尽管它们的脱氨活性是发挥其功能的关键， 生物学功能，APOBEC酶可以偶然突变时，适当的调控是不 这可能导致人类疾病，如免疫缺陷和癌症。我们长久以来- 术语目标是了解APOBEC细胞功能的结构/功能关系 以及它们的抗病毒活性。我们的具体目标是了解APOBEC的结构基础， 功能和底物特异性和抗HIV和抗病毒的机制 活动，特别关注APOBEC 3亚家族成员，这些成员具有强烈的抗- 逆转录病毒和抗艾滋病毒活动。这项研究的结果将提供有价值的 了解APOBEC酶家族的分子细节和 底物特异性的机制，其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（如癌症）提供治疗。

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.