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T cell and B cell antigen receptors share a conserved core transmembrane structure
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2022-11-21 , DOI: 10.1073/pnas.2208058119
Samyuktha Ramesh 1, 2 , Soohyung Park 3, 4, 5 , Wonpil Im 3, 4, 5 , Melissa J. Call 1, 2 , Matthew E. Call 1, 2
Affiliation  

The B cell and T cell antigen receptors (BCR and TCR) share a common architecture in which variable dimeric antigen-binding modules assemble with invariant dimeric signaling modules to form functional receptor complexes. In the TCR, a highly conserved T cell receptor αβ (TCRαβ) transmembrane (TM) interface forms a rigid structure around which its three dimeric signaling modules assemble through well-characterized polar interactions. Noting that the key features stabilizing this TCRαβ TM interface also appear with high evolutionary conservation in the TM sequences of the membrane immunoglobulin (mIg) heavy chains that form the BCR’s homodimeric antigen-binding module, we asked whether the BCR contained an analogous TM structure. Using an unbiased biochemical and computational modeling approach, we found that the mouse IgM BCR forms a core TM structure that is remarkably similar to that of the TCR. This structure is reinforced by a network of interhelical hydrogen bonds, and our model is nearly identical to the arrangement observed in the just-released cryo-electron microscopy (cryo-EM) structures of intact human BCRs. Our biochemical analysis shows that the integrity of this TM structure is vital for stable assembly with the BCR signaling module CD79AB in the B cell endoplasmic reticulum, and molecular dynamics simulations indicate that BCRs of all five isotypes can form comparable structures. These results demonstrate that, despite their many differences in composition, complexity, and ligand type, TCRs and BCRs rely on a common core TM structure that has been shaped by evolution for optimal receptor assembly and stability in the cell membrane.

中文翻译:

T 细胞和 B 细胞抗原受体共享一个保守的核心跨膜结构

B 细胞和 T 细胞抗原受体(BCR 和 TCR)共享一个共同的结构,其中可变二聚抗原结合模块与不变二聚信号模块组装形成功能性受体复合物。在 TCR 中,一个高度保守的 T 细胞受体 αβ (TCRαβ) 跨膜 (TM) 界面形成一个刚性结构,其三个二聚体信号模块通过充分表征的极性相互作用围绕该结构组装。注意到稳定此 TCRαβ TM 界面的关键特征在形成 BCR 同源二聚体抗原结合模块的膜免疫球蛋白 (mIg) 重链的 TM 序列中也表现出高度进化保守性,我们询问 BCR 是否包含类似的 TM 结构。使用公正的生化和计算建模方法,我们发现小鼠 IgM BCR 形成了一个与 TCR 非常相似的核心 TM 结构。这种结构通过螺旋间氢键网络得到加强,我们的模型与刚刚发布的完整人类 BCR 的低温电子显微镜 (cryo-EM) 结构中观察到的排列几乎相同。我们的生化分析表明,这种 TM 结构的完整性对于与 B 细胞内质网中的 BCR 信号模块 CD79AB 的稳定组装至关重要,分子动力学模拟表明所有五种同种型的 BCR 都可以形成类似的结构。这些结果表明,尽管它们在组成、复杂性和配体类型方面存在许多差异,
更新日期:2022-11-21
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