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Publication Abstract from PubMed

The B-cell antigen receptor (BCR) is composed of a membrane-bound immunoglobulin (mIg) of class M, D, G, E or A for antigen recognition(1-3) and a disulfide-linked Igalpha and Igbeta heterodimer (Igalpha/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 A resolution and its Fab-deleted form at 3.3 A resolution. At the ectodomain (ECD), the Igalpha/beta heterodimer mainly uses Igalpha to associate with Cmicro3-Cmicro4 domains of one heavy chain (microHC) while leaving the other heavy chain (microHC') empty. The transmembrane domain (TMD) helices of the two microHCs interact with those of the Igalpha/beta heterodimer to form a tight 4-helix bundle. The asymmetry at the TMD prevents the recruitment of two Igalpha/beta heterodimers. Surprisingly, the connecting peptide between the ECD and TMD of microHC intervenes in between those of Igalpha and Igbeta to guide the TMD assembly through striking charge complementarity. Weaker but distinct density for the Igbeta 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.

Structural principles of B-cell antigen receptor assembly.,Dong Y, Pi X, Bartels-Burgahn F, Saltukoglu D, Liang Z, Yang J, Alt FW, Reth M, Wu H Nature. 2022 Oct 13. pii: 10.1038/s41586-022-05412-7. doi:, 10.1038/s41586-022-05412-7. PMID:36228656^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.