Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions.
Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions.
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DOI：
10.4049/jimmunol.2200455
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发表时间：
2022-12-01
影响因子：
4.4
通讯作者：
V. Smider, Vaughn
中科院分区：
文献类型：
--
作者：
Jenkins, Gabrielle Warner;Safonova, Yana;V. Smider, Vaughn
抗体“超长”第三重链互补决定区（CDR H3）似乎是牛抗体所特有的，并且可以使其能够结合较短CDR H3区不能容易地接近的困难表位。多样性集中在CDR H3的“结”结构域中，其由DH基因区段编码并且位于从抗体表面突出很远的β-带状“茎”的顶部。旋钮区域半胱氨酸含量在半胱氨酸总数、序列位置和二硫键模式形成方面是相当多样的。我们研究了生殖系半胱氨酸在产生不同CDR H3结构库中的作用。在核苷酸水平上，DH多态性和相对于种系的缺失之间的关系，以及在结构水平上半胱氨酸和二硫键含量的多样性，被确定。结构多样性是通过（i）具有改变的半胱氨酸位置的DH多态性，（ii）DH缺失和（iii）通过体细胞超突变（SH）产生的新半胱氨酸形成的，体细胞超突变（SH）形成新的独特二硫键以改变结结构。因此，在生殖系和体细胞免疫遗传水平的机制的组合导致在旋钮区半胱氨酸含量的多样性，有助于在旋钮区二硫键模式，环，和抗原结合表面显着的复杂性。
Antibody “ultralong” third heavy chain complementarity-determining regions (CDR H3) appear unique to bovine antibodies and may enable binding to difficult epitopes that shorter CDR H3 regions cannot easily access. Diversity is concentrated in the “knob” domain of the CDR H3, which is encoded by the DH gene segment and sits atop a β-ribbon “stalk” that protrudes far from the antibody surface. Knob region cysteine content is quite diverse in terms of total number of cysteines, sequence position, and disulfide bond pattern formation. We investigated the role of germline cysteines in production of a diverse CDR H3 structural repertoire. The relationship between DH polymorphisms and deletions relative to germline at the nucleotide level, as well as diversity in cysteine and disulfide bond content at the structural level, were ascertained. Structural diversity is formed through (i) DH polymorphisms with altered cysteine positions, (ii) DH deletions and (iii) new cysteines that arise through somatic hypermutation (SH) that form new, unique disulfide bonds to alter the knob structure. Thus, a combination of mechanisms at both the germline and somatic immunogenetic levels result in diversity in knob region cysteine content, contributing to remarkable complexity in knob region disulfide patterns, loops, and antigen binding surface.
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影响因子：
7
作者：
Safonova Y;Shin SB;Kramer L;Reecy J;Watson CT;Smith TPL;Pevzner PA
通讯作者：
Pevzner PA
影响因子：
--
作者：
Haakenson, Jeremy K;Deiss, Thaddeus C;Smider, Vaughn V
通讯作者：
Smider, Vaughn V
DOI：
10.1073/pnas.85.21.8206
发表时间：
1988-11-01
影响因子：
11.1
作者：
KOCKS, C;RAJEWSKY, K
通讯作者：
RAJEWSKY, K
影响因子：
8
作者：
Liljavirta, J.;Ekman, A.;Niku, M.
通讯作者：
Niku, M.
影响因子：
6.7
作者：
Jardine JG;Sok D;Julien JP;Briney B;Sarkar A;Liang CH;Scherer EA;Henry Dunand CJ;Adachi Y;Diwanji D;Hsueh J;Jones M;Kalyuzhniy O;Kubitz M;Spencer S;Pauthner M;Saye-Francisco KL;Sesterhenn F;Wilson PC;Galloway DM;Stanfield RL;Wilson IA;Burton DR;Schief WR
通讯作者：
Schief WR