T cell and B cell antigen receptors share a conserved core transmembrane structure

Ramesh, Samyuktha; Park, Soohyung; Im, Wonpil; Call, Melissa; Call, Matthew E.

doi:10.1073/pnas.2208058119

Cited by 3 publications

(3 citation statements)

References 94 publications

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“…However, three groups have recently determined the full-length transmembrane structures of the BCR using cryo-EM [16,17,19]. These studies of the murine IgM BCR [19], the human IgG BCR and IgM BCR [16], and a second study of the human IgM BCR (Figure 2) [17], confirmed previous biochemical, fluorescence resonance energy transfer, computational modelling and experimentally guided modelling [31][32][33], showing the F ab arms in a Y shape free of the CD79a/CD79b heterodimer bound to the mIg F c domain with 1:1 stoichiometry [34]. The CD79a/CD79b heterodimer consists of an extracellular domain, a linker and a transmembrane domain.…”

Section: B Cell Receptor Structuresupporting

confidence: 59%

“…The linker peptide (Lµ B ) passes through an "O-ring" formed between CD79a and CD79b that introduces the ECD into the plasma membrane [16,17], where the TM helices form a compact bundle dominated by van der Waals forces and several hydrogen bonds [16,17,19]. Connecting the IgM linker region to CD79a/CD79b though a space in the heterodimer supports the theory that the BCR is assembled in the endoplasmic reticulum [31]. The cytoplasmic tails of the BCR subunits were not identified, suggesting that they are structurally flexible and difficult to characterize using cryo-EM.…”

Section: B Cell Receptor Structurementioning

confidence: 72%

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Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

Bhattacharyya

Christopherson

Skarratt

et al. 2023

Cancers

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B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases.

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Section: B Cell Receptor Structuresupporting

confidence: 59%

Section: B Cell Receptor Structurementioning

confidence: 72%

Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

Bhattacharyya

Christopherson

Skarratt

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…Adaptive immunity is mediated by repertoires of T cell receptors (TCRs) and B cell receptors (BCRs) expressed on the surfaces of T and B cells, respectively 11 . Due to somatic recombination of V(D)J genes, the potential diversity of adaptive immune receptor repertoires far exceeds the number of B or T cells in any one individual.…”

Section: Introductionmentioning

confidence: 99%

BCR, not TCR, repertoire diversity is associated with favorable COVID-19 prognosis

Paran,

Oyama,

Khasawneh

et al. 2024

Preprint

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The SARS-CoV-2 pandemic has had a widespread and severe impact on society, yet there have also been instances of remarkable recovery, even in critically ill patients. In this study, we used single-cell RNA sequencing to analyze the immune responses in recovered and deceased COVID-19 patients during moderate and critical stages. The study included three unvaccinated patients from each outcome category. Although expanded T cell receptor (TCR) clones were predominantly SARS-CoV-2-specific, they represented only a small fraction of the total repertoire in all patients. In contrast, while deceased patients exhibited monoclonal B cell receptor (BCR) expansions without COVID-19 specificity, survivors demonstrated diverse and specific BCR clones. These findings suggest that neither TCR diversity nor BCR monoclonal expansions are sufficient for viral clearance and subsequent recovery. Differential gene expression analysis revealed that protein biosynthetic processes were enriched in survivors, but that potentially damaging mitochondrial ATP metabolism was activated in the deceased. This study underscores that BCR repertoire diversity, but not TCR diversity, correlates with favorable outcomes in COVID-19.

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Deep mutational scanning reveals transmembrane features governing surface expression of the B cell antigen receptor

Ramesh,

Go,

Call

et al. 2024

Front. Immunol.

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B cells surveil the body for foreign matter using their surface-expressed B cell antigen receptor (BCR), a tetrameric complex comprising a membrane-tethered antibody (mIg) that binds antigens and a signaling dimer (CD79AB) that conveys this interaction to the B cell. Recent cryogenic electron microscopy (cryo-EM) structures of IgM and IgG isotype BCRs provide the first complete views of their architecture, revealing that the largest interaction surfaces between the mIg and CD79AB are in their transmembrane domains (TMDs). These structures support decades of biochemical work interrogating the requirements for assembly of a functional BCR and provide the basis for explaining the effects of mutations. Here we report a focused saturating mutagenesis to comprehensively characterize the nature of the interactions in the mIg TMD that are required for BCR surface expression. We examined the effects of 600 single-amino-acid changes simultaneously in a pooled competition assay and quantified their effects by next-generation sequencing. Our deep mutational scanning results reflect a feature-rich TMD sequence, with some positions completely intolerant to mutation and others requiring specific biochemical properties such as charge, polarity or hydrophobicity, emphasizing the high value of saturating mutagenesis over, for example, alanine scanning. The data agree closely with published mutagenesis and the cryo-EM structures, while also highlighting several positions and surfaces that have not previously been characterized or have effects that are difficult to rationalize purely based on structure. This unbiased and complete mutagenesis dataset serves as a reference and framework for informed hypothesis testing, design of therapeutics to regulate BCR surface expression and to annotate patient mutations.

show abstract

T cell and B cell antigen receptors share a conserved core transmembrane structure

Cited by 3 publications

References 94 publications

Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

BCR, not TCR, repertoire diversity is associated with favorable COVID-19 prognosis

Deep mutational scanning reveals transmembrane features governing surface expression of the B cell antigen receptor

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