Abstract
B lymphocytes use B cell receptors (BCRs) to recognize antigens. It is still not clear how BCR transduces antigen-specific physical signals upon binding across cell membrane for the conversion to chemical signals, triggering downstream signaling cascades. It is hypothesized that through a series of conformational changes within BCR, antigen engagement in the extracellular domain of BCR is transduced to its intracellular domain. By combining site-specific labeling methodology and FRET-based assay, we monitored conformational changes in the extracellular domains within BCR upon antigen engagement. Conformational changes within heavy chain of membrane-bound immunoglobulin (mIg), as well as conformational changes in the spatial relationship between mIg and Igβ were observed. These conformational changes were correlated with the strength of BCR activation and were distinct in IgM- and IgG-BCR. These findings provide molecular mechanisms to explain the fundamental aspects of BCR activation and a framework to investigate ligand-induced molecular events in immune receptors.
Highlights
Recognition of antigen by B cell receptor (BCR) initiates B cell activation, which lead to the production of protective antibodies against pathogens (Kurosaki et al, 2010)
Q: quench; DQ: dequench. (E–H) FLIM-fluorescence resonance energy transfer (FRET) to measure the FRET efficiency between CoA 488 and ReAsH of dually tagged VRC01-IgM-BCR expressed in 293T cells stimulated by V51 monomer antigen. (E) Representative FLIM images of V51-activated and nonactivated 293T cells stained by donor only (CoA 488) or stained by donor and acceptor (CoA 488 + ReAsH) were shown
B cell activation is triggered by BCR-antigen engagement
Summary
Recognition of antigen by B cell receptor (BCR) initiates B cell activation, which lead to the production of protective antibodies against pathogens (Kurosaki et al, 2010). Antigen engagement induces phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in Iga/b by the Src family kinase Lyn, resulting in the triggering of signaling cascades (Pierce and Liu, 2010). Remain unclear is the molecular mechanism through which BCR extracellular antigen binding signal is transmitted across the membrane to the BCR intracellular ITAMs for the purpose of B cell activation. ‘Conformational change model’ has been proposed to explain the initiation of B cell activation, in which it is supposed that through a series of conformational changes within the BCR complex, the interaction of antigen with the extracellular domain of mIg is transduced to the intracellular domain of BCR (Harwood and Batista, 2010)
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