The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity.
The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity.
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DOI：
10.1016/j.virol.2003.08.026
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发表时间：
2003-12
期刊：
影响因子：
3.7
通讯作者：
N. Zhou;Xiaoling Zhang;Xuejun Fan;E. Argyris;Jianhua Fang;E. Acheampong;G. Dubois;R. Pomerantz
中科院分区：
文献类型：
--
作者：
N. Zhou;Xiaoling Zhang;Xuejun Fan;E. Argyris;Jianhua Fang;E. Acheampong;G. Dubois;R. Pomerantz
人类APJ是一种G蛋白偶联的七跨膜受体，在人类中枢神经系统（CNS）中有显著表达，并作为人类免疫缺陷病毒1型（HIV-1）和猿猴免疫缺陷病毒（SIV）进入的辅助受体。动物模型研究表明，APJ及其天然配体apelin在体液稳态的中枢控制、血压和心肌收缩力的调节中发挥重要作用。在这项研究中，我们的特点的N-末端结构域的APJ在与其天然配体和HIV-1包膜糖蛋白的相互作用的结构和功能的决定因素。我们证明了APJ的N-末端结构域的第二个10个残基对于与爱帕琳的结合是至关重要的，而前20个氨基酸在支持HIV-1 gp 120介导的细胞-细胞融合中起着重要作用。通过定点突变，我们已经确定了带负电荷的氨基酸残基Glu 20和Asp 23参与受体和辅助受体功能，但残基Tyr 10和Tyr 11基本上有助于辅助受体功能的T嗜性（CXCR 4）和双嗜性（CXCR 4和CCR 5）HIV-1分离株。因此，本研究为进一步表征APJ-apelin在体外和体内的功能以及设计用于治疗CNS中HIV-1感染的小分子提供了潜在的重要信息。
The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell–cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS.