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 Ig$\alpha$ and Ig$\beta$ heterodimer (Ig$\alpha$/$\beta$) 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 \AA resolution and its Fab-deleted form at 3.3 \AA resolution. At the ectodomain (ECD), the Ig$\alpha$/$\beta$ heterodimer mainly uses Ig$\alpha$ 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 Ig$\alpha$/$\beta$ heterodimer to form a tight 4-helix bundle. The asymmetry at the TMD prevents the recruitment of two Ig$\alpha$/$\beta$ heterodimers. Surprisingly, the connecting peptide between the ECD and TMD of µHC intervenes in between those of Ig$\alpha$ and Ig$\beta$ to guide the TMD assembly through striking charge complementarity. Weaker but distinct density for the Ig$\beta$ 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.