Structural principles of B cell antigen receptor assembly

Nature. 2022 Dec;612(7938):156-161. doi: 10.1038/s41586-022-05412-7. Epub 2022 Oct 13.

Abstract

The B cell antigen receptor (BCR) is composed of a membrane-bound class M, D, G, E or A immunoglobulin for antigen recognition1-3 and a disulfide-linked Igα (also known as CD79A) and Igβ (also known as CD79B) heterodimer (Igα/β) that functions as the signalling entity through intracellular immunoreceptor tyrosine-based activation motifs (ITAMs)4,5. The organizing principle of the BCR remains unknown. Here we report cryo-electron microscopy structures of mouse full-length IgM BCR and its Fab-deleted form. At the ectodomain (ECD), the Igα/β heterodimer mainly uses Igα to associate with Cµ3 and Cµ4 domains of one heavy chain (µHC) while leaving the other heavy chain (µHC') unbound. The transmembrane domain (TMD) helices of µHC and µHC' interact with those of the Igα/β heterodimer to form a tight four-helix bundle. The asymmetry at the TMD prevents the recruitment of two Igα/β heterodimers. Notably, the connecting peptide between the ECD and TMD of µHC intervenes in between those of Igα and Igβ to guide TMD assembly through charge complementarity. Weaker but distinct density for the Igβ ITAM 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Cryoelectron Microscopy*
  • Immunoglobulin Fab Fragments
  • Mice
  • Phosphorylation
  • Protein Domains
  • Receptors, Antigen, B-Cell* / biosynthesis
  • Receptors, Antigen, B-Cell* / chemistry
  • Receptors, Antigen, B-Cell* / metabolism
  • Receptors, Antigen, B-Cell* / ultrastructure
  • Signal Transduction

Substances

  • Receptors, Antigen, B-Cell
  • Immunoglobulin Fab Fragments