小柯机器人

2022年10月13日，美国波士顿儿童医院吴皓等研究人员合作在《自然》杂志发表论文，揭示B细胞抗原受体组装的结构原理。

研究人员表示，B细胞抗原受体（BCR）由膜结合的M、D、G、E或A类免疫球蛋白（mIg）组成，用于识别抗原，并由二硫连接的Igα和Igβ异构体（Igα/β）组成，通过其细胞内基于免疫受体酪氨酸的激活模体（ITAM）发挥信号作用。BCR的组织原理仍然难以捉摸。

研究人员报道了小鼠全长IgM BCR的8.2埃分辨率的冷冻电镜结构和其Fab删除形式的3.3埃分辨率结构。在外域（ECD），Igα/β异构体主要利用Igα与一条重链（µHC）的Cµ3-Cµ4结构域结合，而另一条重链（µHC'）是空的。两个μHC的跨膜结构域（TMD）螺旋与Igα/β异构体的螺旋相互作用，形成一个紧密的4螺旋束。TMD的不对称性阻止了两个Igα/β异构体的招募。

令人惊讶的是，µHC的ECD和TMD之间的连接肽介入到Igα和Igβ之间，通过惊人的电荷互补性引导TMD组装。Igβ的ITAM在TMD旁边的密度较弱但很明显，这表明ITAM的磷酸化有可能被自动抑制。界面分析表明，所有的BCR类别都利用一个通用的组织架构。这项研究为理解B细胞信号和设计针对BCR介导的疾病的合理疗法提供了一个结构平台。

附：英文原文

Title: Structural principles of B-cell antigen receptor assembly

Author: Dong, Ying, Pi, Xiong, Bartels-Burgahn, Frauke, Saltukoglu, Deniz, Liang, Zhuoyi, Yang, Jianying, Alt, Frederick W., Reth, Michael, Wu, Hao

Issue&Volume: 2022-10-13

Abstract: The B-cell antigen receptor (BCR) is composed of a membrane-bound immunoglobulin (mIg) of class M, D, G, E or A for antigen recognition1–3 and a disulfide-linked Igα and Igβ heterodimer (Igα/β) that functions as the signalling entity through their intracellular immunoreceptor tyrosine-based activation motifs (ITAMs)4,5. The organizing principle of the BCR remains elusive. Here we report cryogenic electron microscopy structures of mouse full-length IgM BCR at 8.2 resolution and its Fab-deleted form at 3.3 resolution. At the ectodomain (ECD), the Igα/β heterodimer mainly uses Igα to associate with Cμ3-Cμ4 domains of one heavy chain (μHC) while leaving the other heavy chain (μHC’) empty. The transmembrane domain (TMD) helices of the two μHCs interact with those of the Igα/β heterodimer to form a tight 4-helix bundle. The asymmetry at the TMD prevents the recruitment of two Igα/β heterodimers. Surprisingly, the connecting peptide between the ECD and TMD of μHC intervenes in between those of Igα and Igβ to guide the TMD assembly through striking charge complementarity. Weaker but distinct density for the Igβ ITAMs nestles next to the TMD, suggesting potential autoinhibition of ITAM phosphorylation. Interfacial analyses suggest that all BCR classes utilize a general organizational architecture. Our studies provide a structural platform for understanding B-cell signalling and designing rational therapies against BCR-mediated diseases.

DOI: 10.1038/s41586-022-05412-7

Source: https://www.nature.com/articles/s41586-022-05412-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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