Bovine IgM antibodies with exceptionally long complementarity-determining region 3 of the heavy chain share unique structural properties conferring restricted VH+Vλ pairings
Bovine IgM antibodies with exceptionally long complementarity-determining region 3 of the heavy chain share unique structural properties conferring restricted VH+Vλ pairings
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DOI：
10.1093/intimm/dxg083
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Kaushik, AK
中科院分区：
文献类型：
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作者：
Saini, SS;Farrugia, W;Kaushik, AK
牛 (Bos taurus) 天然存在的抗体库包括一组 IgMlambda 抗体，其重链 (CDR3H) 片段具有极长的互补决定区 3，其中包含多个 Cys 残基。这些大量的CDR3H片段将极大地影响牛IgM结合位点的三级和四级结构。由于抗体的结合位点是由重链和轻链形成的，因此我们分析了与含有超长 CDR3H 的 mu 重链配对的 lambda 轻链的核苷酸序列和结构特性。在具有异常长的 CDR3H 的 IgM 中使用三个 V(lambda)1 基因（V(lambda)1x 和两个新的 V(lambda)1d 和 V(lambda)1e 基因）似乎存在严格的选择压力。 V(lambda)1d 和 V(lambda)1e 基因彼此相似，但与其他 V(lambda)1 基因不同，分为两个密切相关的亚家族。现有的牛V-lambda基因根据核苷酸相似性大于或等于80%分为三个V-lambda基因家族：V(lambda)1、V(lambda)2和V(lambda)3。此外，发现序列中总Ser含量和Ser残基位置的分析足以对牛V(lambda)1亚科进行分类。反刍动物（例如牛、绵羊和山羊）和其他哺乳动物（例如人类和小鼠）的 V-lambda 结构域的 Ser 残基模式有所不同。这些“Ser 签名”可用于追踪 lambda 轻链的趋异进化。有趣的是，轻链互补决定区 3 (CDR3L) 中的 Ser90L 出现在与含有超长 CDR3H 的 V-H 区配对的所有 V-lambda 结构域中。 Ser90L 的结构作用在 V-lambda 结构域的同源模型中得到揭示，即将 CDR3L 的上行多肽保持在 N 端片段和 CDR1L 残基之间相对紧密的空间中。如果与具有极长 CDR3H（大于或等于 48 个残基）的 V-H 结构域配对，V-lambda 结构域的 CDR3L 也占据较小的体积，并且如果 CDR3H 小于或等于 22 个残基，则其构象变化更大并填充更大的体积。因此，这些不寻常的牛抗体中的 lambda 轻链的作用可能是充当极长 CDR3H 区域的相对无特征的支持平台，而这些区域无疑主要参与与抗原的结合。
Naturally occurring antibody repertoires of cattle (Bos taurus) include a group of IgMlambda antibodies with exceptionally long complementarity-determining region 3 of the heavy chain (CDR3H) segments, containing multiple Cys residues. These massive CDR3H segments will greatly influence the tertiary and quaternary structures of the bovine IgM combining sites. As an antibody's combining site is formed by both heavy and light chains, we have analyzed the nucleotide sequences and structural properties of the lambda-light chains that pair with mu-heavy chains containing exceptionally long CDR3H. There appears to be an exquisite selective pressure for the use of three V(lambda)1 genes (V(lambda)1x and two new V(lambda)1d and V(lambda)1e genes) in IgM with unusually long CDR3H. The V(lambda)1d and V(lambda)1e genes are similar to each other, but diverge from the other V(lambda)1 genes into two closely related subfamilies. The available bovine V-lambda genes are classified into three V-lambda gene families: V(lambda)1, V(lambda)2 and V(lambda)3 based on nucleotide similarity greater than or equal to80%. Further, analysis of total Ser content and positions of Ser residues in the sequences was found to be sufficient to classify the cattle V(lambda)1 subfamilies. Patterns of Ser residues differ for V-lambda domains from ruminant species (e.g. cattle, sheep and goats) and other mammals (e.g. humans and mice). These 'Ser signatures' can be used to track divergent evolution in lambda-light chains. Interestingly, Ser90L in complementarity-determining region 3 of the light chain (CDR3L) occurred in all V-lambda domains that pair with V-H regions containing exceptionally long CDR3H. A structural role for Ser90L was revealed in homology models of V-lambda domains, i.e. to hold the ascending polypeptide of CDR3L in a relatively tight space between the N-terminal segment and residues from CDR1L. The CDR3L of V-lambda domains also occupied smaller volumes if paired to V-H domains with extremely long CDR3H (greater than or equal to48 residues), and were more variable in their conformation and filled larger volumes if CDR3Hs were less than or equal to22 residues. Thus, the role of the lambda-light chains in these unusual cattle antibodies is probably to act as a relatively featureless supporting platform for the extremely long CDR3H regions, which undoubtedly are dominantly involved in binding to an antigen.