Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary immune response
Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary immune response
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DOI：
10.1016/j.immuni.2006.02.010
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发表时间：
2006-04-01
期刊：
影响因子：
32.4
通讯作者：
Salunke, DM
中科院分区：
文献类型：
--
作者：
Sethi, DK;Agarwal, A;Salunke, DM
通过使用种系抗体36-65，解决了种系抗体中初级抗体反应的混杂性和构象灵活性之间的相关性。对36-65Fab与三个独立的十二肽的结晶学分析为抗体多样性的产生提供了机械性的见解。四个无抗原的Fab分子提供了抗体CDR构象的定量描述，而三个与结构不同的多肽表位结合的Fab分子呈现共同的副表位构象。每种多肽在抗原结合部位都显示出不同的空间足迹。然而，涉及两个共享残基的构象特异性锁也与半抗原结合有关，是可识别的。与半抗原不同，这些多肽与经历体细胞突变的残基相互作用，这表明在亲和力成熟过程中可能存在一种排除“非特异性”抗原的机制。在生殖系抗体的常见副表位构象中观察到的不同表位的多种结合模式揭示了一种简单而优雅的扩大初级抗体库的机制。
Correlation between the promiscuity of the primary antibody response and conformational flexibility in a germline antibody was addressed by using germline antibody 36-65. Crystallographic analyses of the 36-65 Fab with three independent dodecapeptides provided mechanistic insights into the generation of antibody diversity. While four antigen-free Fab molecules provided a quantitative description of the conformational repertoire of the antibody CDRs, three Fab molecules bound to structurally diverse peptide epitopes exhibited a common paratope conformation. Each peptide revealed spatially different footprints within the antigen-combining site. However, a conformation-specific lock involving two shared residues, which were also associated with hapten binding, was discernible. Unlike the hapten, the peptides interacted with residues that undergo somatic mutations, suggesting a possible mechanism for excluding "nonspecific" antigens during affinity maturation. The observed multiple binding modes of diverse epitopes within a common paratope conformation of a germline antibody reveal a simple, yet elegant, mechanism for expanding the primary antibody repertoire.