Dynamics and activation of membrane-bound B cell receptor assembly

Journal Article · 12 February 2025 · Communications Biology

DOI: https://doi.org/10.1038/s42003-025-07478-1 · OSTI ID:2523984

Do, Hung N.  ^[1]; Zhao, Mingfei ^[2]; Alam, S. Munir ^[3]; Gnanakaran, S.  ^[1]

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1. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
2. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); University of Alabama, Tuscaloosa, AL (United States)
3. Duke University School of Medicine, Durham, NC (United States)

B-cell receptor (BCR) complexes are expressed on the surface of a B-cell and are critical in antigen recognition and modulating the adaptive immune response. Even though the relevance of antibodies has been known for almost a hundred years, the antigen-dependent activation mechanism of B-cells has remained elusive. Several models have been proposed for BCR activation, including cross-linking, conformation-induced oligomerization, and dissociation activation models. Recently, the first cryo-EM structures of the human B-cell antigen receptor of the IgM and IgG isotypes have been published that validates the asymmetric organization of the BCR complex. Here, we carry out extensive molecular dynamics simulations to probe the conformational changes upon antigen binding and the influence of the membrane lipids. We identify two critical dynamical events that could be associated with antigen-dependent activation of BCR. First, antigen binding causes increased flexibility in regions distal to the antigen binding site. Second, antigen binding alters the rearrangement of IgM transmembrane helices, including the relative interaction of Igα/Igβ that mediates intracellular signaling. Furthermore, these transmembrane rearrangements lead to changes in localized lipid composition. Our work indirectly supports the conformational-change induced models of BCR activation and contributes to the understanding of the antigen-dependent activation mechanism of BCRs.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
• Grant/Contract Number: 89233218CNA000001
• OSTI ID: 2523984
• Report Number(s): LA-UR--24-26941
• Journal Information: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 8; ISSN 2399-3642
• Publisher: Springer NatureCopyright Statement
• Country of Publication: United States
• Language: English