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

The B cell antigen receptor (BCR) plays an essential role in all phases of B cell development. Here we show that the extracellular domains of murine and human Ig beta form an I-set immunoglobulin-like structure with an interchain disulfide between cysteines on their G strands. Structural and sequence analysis suggests that Ig alpha displays a similar fold as Ig beta. An Ig alpha beta heterodimer model was generated based on the unique disulfide-bonded Ig beta dimer. Solution binding studies showed that the extracellular domains of Ig alpha beta preferentially recognize the constant region of BCR with chain specificity, suggesting a role for Ig alpha beta to enhance BCR mu chain signaling. Cluster mutations on Ig alpha, Ig beta, and a membrane-bound form of immunoglobulin (mIgM) based on the structural model identified distinct areas of potential contacts involving charged residues on both subunits of the coreceptor and the C mu 4 domain of mIgM. These studies provide the first structural model for understanding BCR function.