COOH terminus of membrane IgM is essential for an antigen-specific induction of some but not all early activation events in mature B cells.

Parikh, V S; Nakai, Chieko; Yokota, Sandra J.; Bankert, Richard B.; Tucker, Philip W.

doi:10.1084/jem.174.5.1103

Cited by 18 publications

(10 citation statements)

References 46 publications

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“…Antigen presentation first demands endocytosis of ligandreceptor complexes and then routing of these complexes through a defined endocytic pathway. Previously, we have shown that endocytosis of ligand-receptor complexes does not depend upon the # COOH terminus (16). However, as presented here, the complete TM domain is essential for the ultimate outcome of this process, measured as activation of T cells.…”

Section: Discussionsupporting

confidence: 55%

“…The extracellular NH2 terminus of mIgM endows it with antigen specificity, whereas the membrane-associated COOH terminus, in concert with associated proteins, appears to be 1 Abbreviations used in this pala, r: DSM, domain shuffle mutagenesis; HEL, hen egg lysozyme; Id, idiotype; mIgM, membrane immunoglobulin M; PKC, protein kinase C; TM, transmembranal. involved in initiating the cascade of reactions mentioned above (14). We have shown that the COOH terminus is required for antigen-specific induction of intraceilular Ca 2 + levels, induction of immediate early gene messages, and growth arrest in CH33 cells (15), but not for endocytosis of ligandreceptor complexes (16). This was achieved by replacing 40 amino acids of the COOH terminus of mlgM with the equivalent segment from the COOH terminus of MHC class II I-Abol (17).…”

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confidence: 99%

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Differential structure-function requirements of the transmembranal domain of the B cell antigen receptor.

Parikh

Bishop

Liu

et al. 1992

The Journal of Experimental Medicine

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SummaryBy generating phosphorylcholine (PC)-specific, wild-type (#), and chimeric (/z-I-Ao 0 antigen receptor transfectants of mature B cells, we have shown that the COOH terminus of the/z heavy chain is essential for three major functions: immediate signal transduction (measured as changes in intracdlular Ca2+), antigen presentation, and induction of immunoglobulin M secretion. A more detailed analysis of structural requirements of the COOH-terminal domains contributing to these functions was achieved by systematically replacing the spacer, cytoplasmic, and transmembranal domains of the/z-I-Aol chimeric chain with those of/~. Using this rescue approach, we show that the carboxyl two-thirds of the transmembranal domain (proximal to the cytoplasmic domain) is required for induction of intracellular Ca 2 +, whereas the complete transmembranal domain is required for the function of antigen presentation but is dispensable for induction of antibody secretion.

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Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 99%

Differential structure-function requirements of the transmembranal domain of the B cell antigen receptor.

Parikh

Bishop

Liu

et al. 1992

The Journal of Experimental Medicine

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“…Although these experiments suggest an important role for the Igol-IgB complex in signal transduction, the key questions of how the Igs are linked to the associated proteins, and whether Igct and Ig3 mediate signaling in B cells have not been resolved. To address these issues we have examined B cell lines that carry Igs with specific transmembrane mutations that impede signal transduction (14)(15)(16)(17).…”

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confidence: 99%

Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.

Sanchez

Misulovin

Burkhardt

et al. 1993

The Journal of Experimental Medicine

222

141

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SummaryImmunoglobulin (Ig) antigen receptors are composed of a noncovalently-associated complex of Ig and two other proteins, Igo~ and Ig3. The cytoplasmic domain of both of these Ig associated proteins contains a consensus sequence that is shared with the signaling proteins of the T cell and Fc receptor. To test the idea that Igc~-IgB heterodimers are the signaling components of the Ig receptor, we have studied Ig mutations that interfere with signal transduction. We find that specific mutations in the transmembrane domain of Ig that inactivate Ca 2+ and phosphorylation responses also uncouple IgM from Igoe-Ig/3. These results define amino acid residues that are essential for the assembly of the Ig receptor. Further, receptor activity can be fully reconstituted in Ca 2+ flux and phosphorylation assays by fusing the cytoplasmic domain of Igct with the mutant Igs. In contrast, fusion of the cytoplasmic domain of Ig~ to the inactive Ig reconstitutes only Ca z+ responses. Thus, Igor and IgB are both necessary and sufficient to mediate signal transduction by the Ig receptor in B cells. In addition, our results suggest that IgoL and IgB can activate different signaling pathways.

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“…Several experimental studies showed that mutation of mIgM-Tyr463 and mIgM-Ser464 to valines (YS/VV) results in uncoupling of mIgM from Ig-α/Ig-β (10, 11, 61, 62). Thus, at least one of these two residues probably plays a key role in mIgM—Ig-α/Ig-β association.…”

Section: Resultsmentioning

confidence: 99%

Structural Model of the mIgM B-Cell Receptor Transmembrane Domain From Self-Association Molecular Dynamics Simulations

2018

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Antigen binding to B-cell antigen receptors (BCRs) followed by signaling initiates the humoral immune response. The signaling is intimately coupled to nanoclustering of BCRs and their sorting to specific membrane domains, a process that is ruled by interactions between the BCR transmembrane domain and lipids. While the structure of the extracellular domains of BCRs has been resolved, little is known about the configuration of the constituting four immunoglobulin domains spanning the membrane. Here, we modeled the structure of the transmembrane (TM) domain of the IgM B-cell receptor using self-assembly coarse-grained molecular dynamics simulations. The obtained quaternary structure was validated against available experimental data and atomistic simulations. The IgM-BCR-TM domain configuration shows a 1:1 stoichiometry between the homodimeric membrane-bound domain of IgM (mIgM) and a Ig-α/Ig-β heterodimer. The mIgM homodimer is based on an asymmetric association of two mIgM domains. We show that a specific site of the Ig-α/Ig-β heterodimer is responsible for the association of IgM-BCRs with lipid rafts. Our results further suggest that this site is blocked in small-sized IgM-BCR clusters. The BCR TM structure provides a molecular basis for the previously suggested dissociation activation model of B-cell receptors. Self-assembly molecular dynamics simulations at the coarse-grained scale here proved as a versatile tool in the study of receptor complexes.

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COOH terminus of membrane IgM is essential for an antigen-specific induction of some but not all early activation events in mature B cells.

Cited by 18 publications

References 46 publications

Differential structure-function requirements of the transmembranal domain of the B cell antigen receptor.

Differential structure-function requirements of the transmembranal domain of the B cell antigen receptor.

Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.

Structural Model of the mIgM B-Cell Receptor Transmembrane Domain From Self-Association Molecular Dynamics Simulations

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