B-cell receptor: from resting state to activate

Abstract

B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). 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. However, we understand much less about the BCR before activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. 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. 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. 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. 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.

Figure 1

Schematic diagram of the monomeric B-cell receptor (BCR) and the conformation-induced oligomerization model. In resting B cells, the BCR is a monomer in a closed, inactive (green BCR) conformation at the B-cell surface (left panel). Upon binding of antigen (yellow), a pulling or twisting force (indicated by dashed arrows) induces a conformational change in the Cμ4 domain (indicated in purple) to expose a clustering interface and the opening of the cytoplasmic domains for the initiation of signalling (red BCR).

Figure 2

Schematic diagram of the oligomeric B-cell receptor (BCR) and the dissociation activation model. In resting B cells, the BCR is an auto-inhibited (green BCR) oligomer at the B-cell surface (left panel). Binding of polyvalent antigen (yellow) promotes the dissociation of BCR oligomers and the exposure of immunoreceptor tyrosine-based activation motif residues for phosphorylation and signalling (red BCR).

Figure 3

Schematic diagram of the collision coupling/dissociation model. In resting B cells (upper panel), the actin cytoskeleton defines the diffusion dynamics of the B-cell receptor (BCR); there are both mobile (indicated by long dashed arrow) and immobile (short dashed arrow) BCR. It is not known from single particle tracking studies if the BCR is a monomer or in a higher order structure (grey BCR). Upon alteration of the actin cytoskeleton (lower panels), in the absence of any ligand, BCR signalling can be initiated (red BCR). The collision coupling model proposes that the actin cytoskeleton may limit the interaction between the BCR and functional co-elements such as a key co-receptor (purple); hence, alteration of the diffusion barrier releases the BCR leading to an increase in BCR diffusion and so to an increase in the probability that the BCR will encounter a functional co-element. Alternatively, the actin cytoskeleton may immobilize BCR and inhibitory molecules (blue) together and alteration of actin releases this inhibitory interaction.