Structural and Functional Roles of Transmembrane Domains in B-cell Receptor Signalling

B 细胞受体信号转导中跨膜结构域的结构和功能作用

• 批准号: MR/P022995/1
• 负责人: Ann Dixon
• 金额: $ 47.31万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022995%2F1
• 关键词: Structural; Functional; Roles; Transmembrane; Domains

The B-cell receptor (BCR) complex, comprised of an antigen-binding subunit (membrane immunoglobulin, mIg) and a signalling subunit (the CD79a-b heterodimer), is one of the most important immune receptors in humans and controls B-cell development, activity, selection and death. Yet the mechanism of BCR signalling remains a matter of speculation, partly because of a lack of atomic-level structural data that reveals regions of the complex critical for functional receptor assembly, transport, and signal transmission, namely the transmembrane domains (TMDs). We hypothesise that the TMDs of the three proteins in the BCR complex are mediators of strong and specific (yet uncharacterised) interactions, and outline here work that would yield a molecular-level description of the structures and interactions of the BCR TMDs for the first time. Our hypothesis is based on reports dating back over 25 years which implicate the TM domains as sites of functionally essential protein-protein and protein-lipid interactions, but have thus far not revealed a molecular level understanding of this role. This proposal outlines a molecular-level, biophysical investigation of the structures and interactions of the BCR TMDs, which we will use to design molecules to modulate BCR function. Specifically, we will (i) characterise the strength and sequence dependence of TMD interactions within and between components of the BCR complex in a natural membrane, (ii) utilise a panel of biophysical methods to characterise the structure, stability, stoichiometry and atomic details of TMD interactions in multiple (synthetic) lipid environments, and (iii) use this new information to design and test ability of molecules to disrupt interactions and modify BCR signalling and function in situ. This work will yield the first map of interactions between the BCR TMDs and the first structural data for the BCR TMDs in different lipid environments, thus enhancing our mechanistic understanding of BCR signalling and supporting efforts in basic immunology. The molecules we design would act as a proof of concept that BCR modulation is possible using this approach, and provide a platform for a more comprehensive drug discovery programme in the future towards new theraputic treatments for autoimmune diseases, B-cell leukaemias and lymphomas.

B 细胞受体 (BCR) 复合物由抗原结合亚基（膜免疫球蛋白，mIg）和信号亚基（CD79a-b 异二聚体）组成，是人类最重要的免疫受体之一，控制 B 细胞发育、活动、选择和死亡。然而，BCR 信号传导机制仍然是一个推测问题，部分原因是缺乏原子级结构数据，无法揭示对功能性受体组装、运输和信号传输至关重要的复合体区域，即跨膜结构域 (TMD)。我们假设 BCR 复合物中三种蛋白质的 TMD 是强而特异（尚未表征）相互作用的介体，并在此概述了首次对 BCR TMD 的结构和相互作用进行分子水平描述的工作。我们的假设基于 25 年前的报告，这些报告暗示 TM 结构域是功能上必需的蛋白质-蛋白质和蛋白质-脂质相互作用的位点，但迄今为止尚未揭示对这一作用的分子水平理解。该提案概述了 BCR TMD 的结构和相互作用的分子水平生物物理学研究，我们将用它来设计调节 BCR 功能的分子。具体来说，我们将 (i) 表征天然膜中 BCR 复合物成分内部和成分之间 TMD 相互作用的强度和序列依赖性，(ii) 利用一组生物物理方法来表征 BCR 复合物的结构、稳定性、化学计量和原子细节多种（合成）脂质环境中的 TMD 相互作用，以及 (iii) 使用这些新信息来设计和测试分子破坏相互作用并原位修改 BCR 信号传导和功能的能力。这项工作将产生第一张 BCR TMD 之间相互作用的图谱以及 BCR TMD 在不同脂质环境中的第一个结构数据，从而增强我们对 BCR 信号传导的机制理解并支持基础免疫学方面的工作。我们设计的分子将作为概念证明，证明使用这种方法可以进行 BCR 调节，并为未来更全面的药物发现计划提供一个平台，以开发针对自身免疫性疾病、B 细胞白血病和淋巴瘤的新治疗方法。

项目成果

Molecular Basis of Selectivity and Activity for the Antimicrobial Peptide Lynronne-1 Informs Rational Design of Peptide with Improved Activity.

• DOI: 10.1002/cbic.202100151
• 发表时间: 2021-07-15
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Jayawant ES;Hutchinson J;Gašparíková D;Lockey C;Pruñonosa Lara L;Guy C;Brooks RL;Dixon AM
• 通讯作者: Dixon AM