Crystal structure of a conformation-dependent rabbit IgG Fab specific for amyloid prefibrillar oligomers
Crystal structure of a conformation-dependent rabbit IgG Fab specific for amyloid prefibrillar oligomers
复制标题
DOI：
10.1016/j.bbagen.2012.08.016
复制
发表时间：
2012-12-01
影响因子：
3
通讯作者：
Luecke, Hartmut
中科院分区：
文献类型：
--
作者：
Arai, Hiromi;Glabe, Charles;Luecke, Hartmut
背景：虽然兔抗体在研究中被广泛使用，但尚未报道兔抗原结合片段（Fab）的结构。M204是一种兔单克隆抗体，其识别由许多不同的淀粉样蛋白生成序列形成的前原纤维淀粉样蛋白寡聚体所共有的通用表位。淀粉样蛋白低聚物被广泛怀疑是几种年龄相关的神经退行性疾病（如阿尔茨海默病）发病机制的主要致病因子。这些淀粉样蛋白寡聚体的详细结构尚不清楚，构象依赖性单克隆抗体识别通用表位的机制也不清楚。方法：作为了解构象依赖性抗体识别机制的第一步，我们对M204的Fab进行了结晶。晶体结构揭示了M204抗原结合位点的细节和兔Fab所特有的功能，例如其轻链上的结构域间二硫键。一般意义：基于M204抗原结合位点的结构特征，我们排除了在许多淀粉样蛋白原纤维结构中发现的“空间拉链”形成，作为抗体-抗原识别的机制。第一个兔免疫球蛋白Fab结构的细节也可能有助于开发兔单克隆抗体的潜力，用于开发人源化兔抗体作为治疗剂。(C)2012 Elsevier B. V.保留所有权利。
Background: Although rabbit antibodies are widely used in research, no structures of rabbit antigen-binding fragments (Fab) have been reported. M204 is a rabbit monoclonal antibody that recognizes a generic epitope that is common to prefibrillar amyloid oligomers formed from many different amyloidogenic sequences. Amyloid oligomers are widely suspected to be a primary causative agent of pathogenesis in several age-related neurodegenerative diseases, such as Alzheimer's disease. The detailed structure of these amyloid oligomers is not known nor is the mechanism for the recognition of the generic epitope by conformation-dependent monoclonal antibodies.Method: As a first approach to understanding the mechanism of conformation-dependent antibody recognition, we have crystallized the Fab of M204.Results: We have determined the structure of the Fab of M204 at 1.54 angstrom resolution. The crystal structure reveals details of the M204 antigen combining site and features unique to rabbit Fabs such as an interdomain disulfide bond on its light chain.General significance: Based on the structural features of the antigen-combining site of the M204, we rule out a "steric zipper" formation, as found in numerous amyloid fibril structures, as a mechanism of antibody-antigen recognition. The details of the first rabbit immunoglobulin Fab structure might also be useful for exploiting the potential of rabbit monoclonal antibodies for the development of humanized rabbit antibodies as therapeutic agents. (C) 2012 Elsevier B.V. All rights reserved.