Role of the extracellular and transmembrane domain of Ig-alpha/beta in assembly of the B cell antigen receptor (BCR).

The B cell antigen receptor (BCR) is expressed on the surface of B-lymphocytes where it binds antigen and transmits signals that regulate B cell activation, growth and differentiation. The BCR is composed of membrane IgM (mIgM) and two signaling proteins, Ig-alpha and Ig-beta. If either of the signaling proteins is not expressed, the incomplete mIgM-containing BCR will not traffic to the cell surface. Our hypothesis is that specific protein:protein interactions between both the extracellular and transmembrane (TM) regions of Ig-alpha and Ig-beta are necessary for receptor assembly, cell surface expression and effective signaling to support the proper development of B cells. While previous work has shown the importance of the TM region in BCR assembly, this study indicates that a heterodimer of the extracellular domains of Ig-alpha and Ig-beta are also required for proper association with mIgM. Cell lines expressing mutated Ig-alpha proteins that did not heterodimerize with Ig-beta in the extracellular and TM domains were unable to properly assemble the BCR. Conversely, an Ig-alpha mutant with an Ig-beta cytoplasmic tail (Cbeta (alpha/alpha/beta)) was able to assemble with the rest of the BCR, in particular with Ig-beta, and traffic to the cell surface. Thus, both the extracellular and TM regions of the Ig-alpha/Ig-beta must be properly associated in order for the BCR to assemble.