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Cited by 2Protein Structure and DynamicsT-cell and B-cell ImmunologyLipid Membrane Structure and Behavior

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Dynamics and activation of membrane-bound B cell receptor assembly

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Do, Hung N., Zhao, Mingfei, Alam, S. Munir, Gnanakaran, S.·2025·Communications Biology
DOI 10.1038/s42003-025-07478-1PMC PMC11825855

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Abstract

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.

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Fig. 1 Simulation systems of the model B cell receptor (BCR) complexes. a The CH31 BCR in the complex membrane. b The CH31 BCR bound by a monomer of HIV-1 envelope protein (HIV-1 Env) in the complex membrane. The Fab heavy chains are colored red, Fab light chains are colored blue, Fc domains are colored cyan, transmembrane helices of BCR are colored green, Igα is colored magenta, Igβ is colored brown, and the HIV-1 Env is colored gray. The phosphatidylcholine (POPC) molecules are colored light blue, phosphatidylethanolamine (POPE) are colored light orange, palmitoyl sphingomyelin (PSM) are colored light pink, diacylglycerols (DAGL) are colored pale green, cholesterols (CHOL) are colored wheat, and ceramides (CER3) are colored pale cyan.
Fig. 1 Simulation systems of the model B cell receptor (BCR) complexes. a The CH31 BCR in the complex membrane. b The CH31 BCR bound by a monomer of HIV-1 envelope protein (HIV-1 Env) in the complex membrane. The Fab heavy chains are colored red, Fab light chains are colored blue, Fc domains are colored cyan, transmembrane helices of BCR are colored green, Igα is colored magenta, Igβ is colored brown, and the HIV-1 Env is colored gray. The phosphatidylcholine (POPC) molecules are colored light blue, phosphatidylethanolamine (POPE) are colored light orange, palmitoyl sphingomyelin (PSM) are colored light pink, diacylglycerols (DAGL) are colored pale green, cholesterols (CHOL) are colored wheat, and ceramides (CER3) are colored pale cyan.CC BY-NC-ND · PubMed Central
Fig. 2 Changes in the system flexibility as measured by the changes in root-mean- square fluctuations (∆RMSF) upon antigen binding to the BCR. The important domains that showed significant dynamic changes upon antigen binding in the BCR in (a) are zoomed in (b, c). A color scale of blue (-3.0)—white (0.0)—red (3.0) is used to show the magnitudes of ∆RMSFs. The HIV-1 Env is colored gray.
Fig. 2 Changes in the system flexibility as measured by the changes in root-mean- square fluctuations (∆RMSF) upon antigen binding to the BCR. The important domains that showed significant dynamic changes upon antigen binding in the BCR in (a) are zoomed in (b, c). A color scale of blue (-3.0)—white (0.0)—red (3.0) is used to show the magnitudes of ∆RMSFs. The HIV-1 Env is colored gray.CC BY-NC-ND · PubMed Central
Fig. 3 Effects of antigen binding to the BCR on the global tilt angles of the transmembrane helices (including TM1, TM2, and the Igα/ Igβ heterodimer) normal to membrane (z-axis) as calculated from the MD simulations of the BCR complexes. a The global tilt angle was defined as the angle formed by the transmembrane helices and the z- axis (which was perpendicular to the membrane plane). b The averages and standard deviations of the global tilt angles of the transmembrane helices calculated from the MD simulations of the BCR complexes. The bars for the BCR without and with antigen bound are colored blue and orange, respectively. The error bars represent the standard deviations. The p-values were calculated using the unpaired student’s t-test with the numbers of samples being the numbers of simulation replicas (N = 5) and shown on top of the bar graphs. The average tilt angles for each simulation replica are included as red and green dots for the BCR without and with antigen bound, respectively. c The distributions of the global tilt angles of the transmembrane helices calculated from the MD simulations of the BCR complexes shown as boxplots. The antigen was found to mostly interact with the second IgM subunit (containing TM2, marked by *).
Fig. 3 Effects of antigen binding to the BCR on the global tilt angles of the transmembrane helices (including TM1, TM2, and the Igα/ Igβ heterodimer) normal to membrane (z-axis) as calculated from the MD simulations of the BCR complexes. a The global tilt angle was defined as the angle formed by the transmembrane helices and the z- axis (which was perpendicular to the membrane plane). b The averages and standard deviations of the global tilt angles of the transmembrane helices calculated from the MD simulations of the BCR complexes. The bars for the BCR without and with antigen bound are colored blue and orange, respectively. The error bars represent the standard deviations. The p-values were calculated using the unpaired student’s t-test with the numbers of samples being the numbers of simulation replicas (N = 5) and shown on top of the bar graphs. The average tilt angles for each simulation replica are included as red and green dots for the BCR without and with antigen bound, respectively. c The distributions of the global tilt angles of the transmembrane helices calculated from the MD simulations of the BCR complexes shown as boxplots. The antigen was found to mostly interact with the second IgM subunit (containing TM2, marked by *).CC BY-NC-ND · PubMed Central
Fig. 4 Changes in residue contacts between Igα and Igβ upon binding of the antigen to the membrane bound BCR. a Changes in residue contact frequencies between Igα and Igβ upon HIV-1 Env binding to the BCR. A contact definition of ≤8.0 Å distance between Cα atoms was used. A color scale of blue (-0.2)—white (0)—red (0.2) was used to show the magnitudes of changes in residue contact frequencies. b Representative reduced contacts upon antigen binding in the BCR. c Representative increased contacts upon antigen binding in the BCR. The structural residue contacts colored blue were those that showed decreases in contact frequencies upon antigen binding, whereas those colored red showed increased in contact frequencies upon antigen binding.
Fig. 4 Changes in residue contacts between Igα and Igβ upon binding of the antigen to the membrane bound BCR. a Changes in residue contact frequencies between Igα and Igβ upon HIV-1 Env binding to the BCR. A contact definition of ≤8.0 Å distance between Cα atoms was used. A color scale of blue (-0.2)—white (0)—red (0.2) was used to show the magnitudes of changes in residue contact frequencies. b Representative reduced contacts upon antigen binding in the BCR. c Representative increased contacts upon antigen binding in the BCR. The structural residue contacts colored blue were those that showed decreases in contact frequencies upon antigen binding, whereas those colored red showed increased in contact frequencies upon antigen binding.CC BY-NC-ND · PubMed Central
Fig. 5 Reorganization of the local lipid environments upon antigen binding to the BCR in the complex membrane. a All lipid molecules within 4Å distance of the membrane- peripheral region and membrane-bound helices of the BCR are considered. The numbers of surrounding lipid molecules during the last 100 ns of the AA (b) and CG MD simulations (c) in the complex membrane are shown. The bars for the BCR without and with antigen bound are colored blue and orange, respectively. The error bars represent the standard deviations. The p-values were calculated using the unpaired student’s t-test with the numbers of samples being the numbers of simulation replicas (N = 5) and shown on top of the bar graphs. The average numbers of surrounding lipid molecules for each simulation replica are included as red and green dots for the BCR without and with antigen bound, respectively.
Fig. 5 Reorganization of the local lipid environments upon antigen binding to the BCR in the complex membrane. a All lipid molecules within 4Å distance of the membrane- peripheral region and membrane-bound helices of the BCR are considered. The numbers of surrounding lipid molecules during the last 100 ns of the AA (b) and CG MD simulations (c) in the complex membrane are shown. The bars for the BCR without and with antigen bound are colored blue and orange, respectively. The error bars represent the standard deviations. The p-values were calculated using the unpaired student’s t-test with the numbers of samples being the numbers of simulation replicas (N = 5) and shown on top of the bar graphs. The average numbers of surrounding lipid molecules for each simulation replica are included as red and green dots for the BCR without and with antigen bound, respectively.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Do, H. N., Zhao, M., Alam, S. M., & Gnanakaran, S.
Affiliations
  • Los Alamos National Laboratory (US)
  • Duke University (US)
Corresponding author
Gnanakaran, S.
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2025-02-13
Volume
8
Issue
1
Pages
226-226
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-025-07478-1
PMC
PMC11825855
OpenAlex
W4407535508
Cited by
2
References
3
Citations by year
2026: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (U54-AI170752-01)
  • DOE | National Nuclear Security Administration (89233218CNA000001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
B cell receptor, antigen binding, conformational change, IgM, IgG, membrane lipids, intracellular signaling, molecular dynamics simulation

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Do, H. N., Zhao, M., Alam, S. M., & Gnanakaran, S. (2025). Dynamics and activation of membrane-bound B cell receptor assembly. Communications Biology. https://doi.org/10.1038/s42003-025-07478-1