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VHH CDR-H3 形状是由VH生殖系使用量决定的

Zahra Bahrami Dizicheh¹, I-Ling Chen¹, Patrick Koenig²

¹23andMe, Inc. Therapeutics, 349 Oyster Point Boulevard, South San Francisco, CA, 94080, USA.

Communications biology

|August 19, 2023

概括

驼类重链变量域 (VHHs) 或纳米体是通过CDR-H3循环构造进行分类的. 这种结构与它们的生殖系起源有关,影响抗原结合和免疫谱系的发展.

科学领域:

免疫学免疫学免疫学
结构生物学结构生物学
生物化学生物化学

背景情况:

单抗原结合域,VHHs (纳米体),来自驼类重链抗体,对于诊断,研究和治疗至关重要.
在VHH的结构分析中,基于CDR-H3循环构造,发现了两个主要集群:延伸和扭曲.

研究的目的:

根据CDR-H3形态,对VHH结构进行分类.
研究VHH CDR-H3形状,生殖系起源和抗原结合性质之间的关系.
了解生殖系使用对免疫谱系塑造的影响.

主要方法:

拉玛和阿尔帕卡VHHs的变量域的结构分析.
根据CDR-H3循环形状,将VHH分为结构集群的分类.
在CDR-H3形状,生殖基因使用 (IGHV3-3,IGHV3S53) 和V(D) J重组模式之间的相关性分析.

主要成果:

VHH被分为两个主要的结构组:具有扩展CDR-H3循环的和具有扭曲CDR-H3循环的.
延伸环突出进入溶剂,而扭曲环折叠回框架区域,表现出不同的特性.
CDR-H3形状与生殖系起源有很强的相关性,IGHV3-3衍生抗体显示扭曲形状,IGHV3S53衍生抗体显示扩展形状.
没有观察到V(D) J重组的偏差,这表明选择过程会影响这种相关性.

结论:

VHH CDR-H3 形状受到生殖基因使用的显著影响,而不是V(D) J重组.
这种由生殖线驱动的结构偏差会影响抗原相互作用,并塑造抗体免疫谱.
这些发现增强了对抗体框架特性如何决定免疫谱系多样性和功能的理解.

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