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APOBEC(载脂蛋白B mRNA编辑酶催化多肽)家族 脱氨酶脱氨只在脊椎动物中发现，所有APOBEC3亚家族蛋白都是 只在灵长类动物中发现。通过使胞苷脱氨基导致DNA/RNA上的尿苷发生突变， APOBEC酶通过特异性靶向APOBEC实现多种细胞功能 通过包括空间和时间以及 底物专一性。例如，APOBEC1(A1)特异性地修饰一种蛋白质的mRNA，该蛋白质 在胆汁淤积代谢中发挥作用；AID，APOBEC家族的另一成员，需要 抗体成熟过程，包括体细胞高突变和重组类切换； ApoBEC2(A2)参与心肌和骨骼肌的发育；A3蛋白是一种 亚家族包含7个成员(AA-H)，可以限制外源和内部核酸 对基因组的完整性造成危险，包括内部反转录元件和转座子 以及外部逆转录病毒和其他传染性病毒病原体，如人类 免疫缺陷病毒(HIV)、乙肝病毒(乙肝)。对于像HIV病毒这样的逆转录病毒 克服APOBEC enyzme的抗HIV活性，它们编码一种名为Vif(病毒)的蛋白质 毒力因子)通过解毒素化与APOBEC酶特异性结合并使其失活 退化到一半的时候。即使他们的脱氨活动是摘除他们 生物学功能，APOBEC酶可能在适当的监管不力时发生意外突变 这可能会导致人类的疾病，如免疫功能低下和癌症。我们的长- 学期目标是了解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 底物特异性、抗HIV和抗病毒的功能和机制 活动，特别侧重于APOBEC3亚家族成员具有强烈的抗 逆转录因子和抗艾滋病毒活性。这项拟议研究的结果将提供有价值的 了解APOBEC酶家族分子细节的信息和 底物专一性的机制，可用于潜在的药物开发 为艾滋病毒/艾滋病、免疫紊乱和癌症等其他疾病提供治疗。

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.