Adjustable Locks and Flexible Keys: Plasticity of Epitope-Paratope Interactions in Germline Antibodies
Adjustable Locks and Flexible Keys: Plasticity of Epitope-Paratope Interactions in Germline Antibodies
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DOI：
10.4049/jimmunol.1302143
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发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
Salunke, Dinakar M.
中科院分区：
文献类型：
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作者：
Khan, Tarique;Salunke, Dinakar M.
分析了独立的初级Ab对具有重叠表位的小柔性Ag的Ag识别，以解决在初始相遇期间Ag特异性的决定因素。测定了与种系mAb 36-65复合的两种不同的十二肽Ag（GDPRPSYISHLL和PPYPAWHAPGNI）的晶体结构，并与结合至另一种独立的种系mAb（BBE 6.12H3）的相同Ag的结构进行了比较。对于每种肽Ag，两种种系Ab识别重叠的表位，但在不同的拓扑结构。肽结构不同，两个互补位获得离散的构象，导致不同的表面拓扑结构，在一种模式，可以被描述为可调节的锁和灵活的钥匙。这与成熟的mAb相反，成熟的mAb中已经报道了不同互补位的构象收敛，同时以相似的构象结合到共同的表位。这些结果表明，初级免疫受体库与其成熟的对应物相比是高度通用的。种系和成熟mAb采用不同的机制来识别柔性表位。尽管构象库的保守性是通过亲和力成熟实现的成熟mAb的关键特征，但在Ag相遇的初始阶段，种系mAb保持实质性的可塑性，从而适应广泛的特异性库。
Ag recognition by independent primary Abs against a small flexible Ag with overlapping epitopes was analyzed to address the determinants of Ag specificity during the initial encounter. Crystal structures of two distinct dodecapeptide Ags, GDPRPSYISHLL and PPYPAWHAPGNI, in complex with the germline mAb 36-65 were determined and compared with the structures of the same Ags bound to another independent germlinemAb, BBE6.12H3. For each peptideAg, the two germlinem Abs recognized overlapping epitopes, but in different topologies. The peptide structures differed, and the two paratopes attained discrete conformations, leading to different surface topologies, in a mode that can be described as adjustable locks and flexible keys. This is in contrast to mature mAbs, in which conformational convergence of different paratopes while binding to a common epitope in a similar conformation has been reported. These results suggest that the primary immune receptor repertoire is highly versatile as compared with its mature counterpart. Germline and mature mAbs adopt distinct mechanisms for recognizing a flexible epitope. Whereas conservation of conformational repertoire is a key characteristic of mature mAbs achieved through affinity maturation, the germline mAbs, at the initial stages of Ag encounter, maintain substantial plasticity, accommodating a broad specificity repertoire.