8 This was subsequently confirmed using a quantitative microscopy approach, which compared the ratio of fluorescence intensity of labelled mIg to Igα/Igβ across a range of expression levels. 7 However, this 1 : 2 stoichiometry of BCR : Igα/Igβ was never experimentally tested and subsequent biochemical studies demonstrated that the BCR was composed of a single mIg and one associated Igα/Igβ chain. 6 The BCR complex was originally believed to be composed of a ‘sheath’ of Igα/Igβ that is, each mIg was non-covalently bound on each side to Igα/Igβ chains, thus ‘sheathing’ the mIg. The mIg itself does not contain any signalling motifs but instead is linked to the Igα/Igβ heterodimer, which contains immunoreceptor tyrosine-based activation motifs (ITAM) a conserved sequence of four amino acids in which a tyrosine is separated from a leucine or isoleucine by any two amino acids (YxxL/I) and generally repeated twice in the cytoplasmic domain of ITAM-containing proteins separated by between 7 and 12 amino acids, giving it the signature YxxL 7–12YxxL. The BCR is composed of membrane immunoglobulin (mIg) a structure of four (in the case of IgD) or five (IgM) immunoglobulin domains in the heavy chain linked by a hinge, and a short intracellular domain consisting of just three amino acids: lysine, valine, lysine (KVK). Mature B cells express two BCR isotypes, IgM and IgD. Finally, the collision coupling model suggests that BCR are segregated from activating co-receptors or kinases and activation is associated with changes in BCR mobility on the cell surface, which allows for the functional interaction of these elements. Conversely, the dissociation activation model proposes that BCRs exist in auto-inhibitory oligomers on the resting B-cell surface and binding of antigen promotes the dissociation of the BCR oligomer exposing phosphorylation residues within Igα/Igβ. These models include the conformation-induced oligomerization model, in which binding of antigen to monomeric BCR induces a pulling or twisting force causing conformational unmasking of a clustering interface in the Cμ4 domain. These parameters have important implications for our understanding of the initiation of B-cell activation and will be discussed in the context of current models for BCR activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. However, we understand much less about the BCR before activation. The early molecular events triggered by BCR binding of ligand have been well-characterized both biochemically and using optical microscopy techniques to visualize B-cell activation as it happens. B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR).
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