The Molecular Mechanism of the CD19-CD81 B Cell Co-Receptor Complex

摘要 Tetraspanins由一类四通道跨膜蛋白组成，它获得了各种不同的 哺乳动物生理中的离散但知之甚少的功能，在免疫中发挥重要作用， 神经、心血管、生殖和听觉系统，以及在感染疾病过程、肿瘤 转移和器官系统的发展。Tetraspanins的功能是通过它们的 与配对蛋白直接相互作用，而Tetraspanin最关键的功能之一是调节 通过Tetraspanin分化簇81(CD81)与B细胞相互作用的B细胞信号转导 共受体，分化簇19(CD19)。CD19的表达和信号改变导致B细胞缺陷 细胞发育，并与免疫缺陷、B细胞恶性肿瘤和 自身免疫力。然而，CD81调节CD19的运输和信号传递的机制是 不清楚，主要是因为缺乏结构和生化数据。因此，我建议调查 Tetraspanin调控CD19的分子机制：I)CD19-的结构特征 CD81复合体，以及II)CD19转运到细胞表面和B细胞后信号转导的功能研究 在基于细胞的分析中激活。更好地理解CD19-CD81的分子机制 功能将具有广泛的生物医学意义，为B细胞生物学和信号提供新的见解 转导机制，Tetraspanin功能，以及如何更好地靶向B细胞信号通路 治疗学。 根据F31奖学金，我将接受结构生物学、膜蛋白 在哈佛医学院克鲁斯博士和布莱克洛博士的指导下，生物化学和分析方法的发展 学校。我的技术培训将伴随着实验设计、指导、公共培训 演讲，生物医学伦理，科学写作，以及在科学会议上展示我的研究的机会。 这一培训计划旨在实现成功和富有成效的研究生教育，并将提供 为实现我成为一名独立研究人员的长期目标奠定了坚实的基础 跨膜信号。

Abstract The tetraspanins comprise a class of four-pass transmembrane proteins that have acquired a variety of discrete, yet poorly understood, functions in mammalian physiology, playing essential roles in the immune, nervous, cardiovascular, reproductive, and auditory systems, as well as in infectious disease processes, tumor metastasis, and the development of organ systems. The functions of tetraspanins are mediated through their direct interaction with partner proteins, and one of the most critical functions of a tetraspanin is the regulation of B cell signaling via the interaction between the tetraspanin cluster of differentiation 81 (CD81) and the B cell co-receptor, cluster of differentiation 19 (CD19). Altered expression and signaling of CD19 causes defects in B cell development and has been implicated in the development of immunodeficiency, B cell malignancies, and autoimmunity. However, the mechanism by which CD81 regulates the trafficking and signaling of CD19 is unclear, largely due to a lack of structural and biochemical data. Therefore, I propose to investigate the molecular mechanism of tetraspanin regulation of CD19 through: i) structural characterization of the CD19- CD81 complex, and ii) functional studies of CD19 trafficking to the cell surface and signaling after B cell activation in cell-based assays. A better understanding of the molecular mechanism underlying CD19-CD81 function will have broad biomedical implications, offering novel insights into B cell biology and signal transduction mechanisms, tetraspanin function, and how to better target the B cell signaling pathway for novel therapeutics. Under the F31 fellowship award, I will receive exceptional training in structural biology, membrane protein biochemistry, and assay development under the guidance of Dr. Kruse and Dr. Blacklow at Harvard Medical School. My technical training will be accompanied by training in experimental design, mentorship, public speaking, biomedical ethics, scientific writing, and opportunities to present my research at scientific meetings. This training plan is designed to lead to a successful and productive graduate education and will provide an outstanding foundation for achieving my long-term goal of becoming an independent researcher focused on transmembrane signaling.