Structural and Functional Studies of Igαβ and Its Assembly with the B Cell Antigen Receptor

Abstract

The B cell antigen receptor (BCR) plays an essential role in all phases of B cell development. Here, we show the extracellular domains of murine and human Igβ form an I-set immunoglobulin-like structure with an inter-chain disulfide between cysteines on their G-strands. Structural and sequence analysis suggests that Igα displays similar fold as Igβ. An Igαβ heterodimer model was generated based on the unique disulfide bonded Igβ dimer. Solution binding studies showed that the extracellular domains of Igαβ preferentially recognized the constant region of BCR with the μ-chain specificity, suggesting a role for Igαβ to enhance the BCRμ-chain signaling. Cluster mutations on Igα, Igβ and mIgM based on the structural model identified distinct area of potential contacts involving charged residues on both subunits of the co-receptor and the Cμ4 domain of mIgM. These studies provide the first structural model for understanding BCR function.

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

“…Rather, it seems to be the special features of Igβ that is responsible for this difference. Only Igβ, but not Igα, seems to be able to form a homodimer that is transported to the B‐cell surface in the absence of any other BCR components (Radaev et al , 2010). Indeed, the exposure of Igβ‐only Ramos B cells to anti‐Igβ antibodies induces a calcium flux whereas Igα‐only Ramos B cells did not respond at all to anti‐Igα antibodies.…”

Tonic Signals: Why Do Lymphocytes Bother?

“…Naïve mature follicular B cells uniquely express two different BCR isotypes, IgM and IgD , which are splice isoforms generated from the same primary transcript [17,18]. Since both isotypes have identical antigen-binding Fab domains, and both pair with Igα/β chains to transduce signals into the cell, it has been unclear what unique functions they may serve.…”

The tipping points in the initiation of B cell signalling: how small changes make big differences

“…An important step towards this goal was the recent solution of the structure of a disulphide-linked homodimer of Igβ, which allowed the modelling of an Igα–Igβ heterodimer with the existing structure of the Cα4 domain 59 (Supplementary information S2 (figure)). Combined with solution- binding studies and microcluster mutagenesis analyses, these results predicted an extensive contact surface between membrane-bound immunoglobulin and both Igα and Igβ through multiple charged residues.…”