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Patho-physiological analysis of collagen vascular disease development results from dysfunction of the membrane microdomain, lipid rafts

膜微区、脂筏功能障碍导致胶原血管疾病发生的病理生理学分析

基本信息

批准号：
18591101
负责人：
HONDA Zen-ichiro
金额：
$ 2.49万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

The findings that FcgRIIB, a prototypical negative regulatory immune receptor, has a common structural polymorphism associated with systemic lupus erythematodes at the transmembrane stretch, and that this polymorphism results in a reduction-of-function receptor, have for the first time prevailed the pivotal role of the negative regulatory receptor family in the immuno-surveillance in humans as well as previously underestimated functional significance of transmembrane domain in immune receptors. This study has been aimed at the structural elucidation of the transmembrane interface developed after the productive oligomerization of immune receptors with polyvalent antigens, immune complexes and stimulatory antibodies, and at the further knowledge of the initiation mechanisms of immune receptor signaling. During the study interval supported by the grant, we have for the first time unveiled that FcgRIIA, a counterpart of FcgRIIB with positive regulatory functions, specifically self associate with one another at the N terminus (outer surface) of the transmembrane stretch, and that this association is in fact productive event: dimerization of the receptor with the aid of disulfide bond mutageneis located at the N-terminus augments Lyn activation, Btk activation and Phospholipase C gamma activation without further ligation of the receotir. This model experiments clearly show that there is a specific, productive interface in immune receotor transmembrane domain, and suggest that the interface serves as a novel therapeutic target for the medicines dissociating the functional interface.

FcgRIIB是一种典型的负调节免疫受体，在跨膜拉伸时具有与系统性红斑狼疮相关的常见结构多态，这种多态导致受体功能降低，这一发现首次主导了负调节受体家族在人类免疫监测中的关键作用，以及先前低估了跨膜结构域在免疫受体中的功能意义。本研究旨在阐明免疫受体与多价抗原、免疫复合体和刺激性抗体发生高效齐聚后形成的跨膜界面的结构，并进一步了解免疫受体信号的启动机制。在拨款支持的研究期间，我们首次揭示了FcgRIIA，一个具有正调节功能的FcgRIIB的对应物，特别是在跨膜拉伸的N端(外表面)相互自结合，并且这种联系实际上是生产性事件：借助位于N-端的二硫键突变，受体的二聚化增强了Lyn激活、BTK激活和磷脂酶C伽马激活，而不需要进一步连接受体。这个模型实验清楚地表明，在免疫受体跨膜结构域中存在着一个特定的、富有成效的界面，并表明该界面是药物解离功能界面的一个新的治疗靶点。