Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures
Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures
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DOI：
10.1016/j.jmb.2003.10.007
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发表时间：
2003-12-05
影响因子：
5.6
通讯作者：
Kirkham, PM
中科院分区：
文献类型：
--
作者：
Zemlin, M;Klinger, M;Kirkham, PM
免疫球蛋白连接多样性集中在重链的第三个互补决定区（CDR-H3），该区域通常在抗原结合中起主导作用。小鼠的 CDR-H3 长度范围比人类的短，因此可以推测小鼠的 CDR-H3 长度范围是人类的 CDR-H3 长度范围。为了验证这一假设，我们分析了 4751 个人类和 2170 个小鼠独特的、功能性的、已发表的 CDR-H3 区间。尽管发现酪氨酸、甘氨酸和丝氨酸在这两个物种中占主导地位，但人类序列包含较少的酪氨酸残基、更多的脯氨酸残基和更多的疏水残基（分别为p < 0.001）。虽然氨基酸利用率随 CDR-H3 长度变化的变化在两个物种中遵循相似的趋势，但发现相同长度的小鼠和人类 CDR-H3 间隔彼此不同。这些差异反映了种系多样性的差异以及连接基因序列和体细胞选择的差异。这些因素共同促进小鼠体内产生相当一致的富含酪氨酸的CDR-H3环库，并具有稳定的氢键梯，而人类则产生更加多样化的库，其中包含由种系编码的半胱氨酸残基导致的链内二硫键的存在以及体细胞生成的脯氨酸残基的增强存在而形成的CDR-H3环，从而阻止了氢键梯的形成。因此，尽管假定需要识别相似范围的抗原表位，但鼠类CDR-H3库在其氨基酸组成和其预测的结构范围方面明显不同于其人类对应部分。这些发现代表了一个基准，可以将 CDR-H3 库进行比较，以更好地表征和理解 CDR-H3 库在进化过程中和免疫反应过程中的形成。该信息也可用于合成抗体文库中物种特异性 CDR-H3 序列的设计。 (C) 2003 Elsevier Ltd. 保留所有权利。
Immunoglobulin junctional diversity is concentrated in the third complementarity-determining region of the heavy chain (CDR-H3), which often plays a dominant role in antigen binding. The range of CDR-H3 lengths in mouse is shorter than in human, and thus the murine repertoire could be presumed to be a subset of the human one. To test this presumption, we analyzed 4751 human and 2170 murine unique, functional, published CDR-H3 intervals. Although tyrosine, glycine, and serine were found to predominate in both species, the human sequences contained fewer tyrosine residues, more proline residues, and more hydrophobic residues (p < 0.001, respectively). While changes in amino acid utilization as a function of CDR-H3 length followed similar trends in both species, murine and human CDR-H3 intervals of identical length were found to differ from each other. These differences reflect both divergence of germline diversity and joining gene sequence and somatic selection. Together, these factors promote the production of a rather uniform repertoire in mice of tyrosine-enriched CDR-H3 loops with stabilized hydrogen bond-ladders versus a much more diverse repertoire in human that contains CDR-H3 loops sculpted by the presence of intra-chain disulfide bonds due to germline-encoded cysteine residues as well as the enhanced presence of somatically generated proline residues that preclude hydrogen bond ladder formation. Thus, despite the presumed need to recognize a similar range of antigen epitopes, the murine CDR-H3 repertoire is clearly distinct from its human counter part in its amino acid composition and its predicted range of structures. These findings represent a benchmark to which CDR-H3 repertoires can be compared to better characterize and understand the shaping of the CDR-H3 repertoire over evolution and during immune responses. This information may also be useful for the design of species-specific CDR-H3 sequences in synthetic antibody libraries. (C) 2003 Elsevier Ltd. All rights reserved.