A symmetric geometry of transmembrane domains inside the B cell antigen receptor complex
Gottwick C, He X, Hofmann A, Vesper N, Reth M, Yang J.
B lymphocytes have the ability to sense thousands of structurally different antigens and produce cognate antibodies against these molecules. For this they carry on their surface multiple copies of the B cell antigen receptor (BCR) comprising the membrane-bound immunoglobulin (mIg) molecule and the Igα/Igβ heterodimer functioning as antigen binding and signal transducing components, respectively. The mIg is a symmetric complex of two identical membrane-bound heavy chains (mHC) and two identical light chains. How the symmetric mIg molecule is asymmetrically associated with only one Igα/Igβ heterodimer was a puzzle so far. Here we describe that Ig α- and IgV both carry on one side of their α-helical transmembrane domain a conserved amino acid motif. By a mutational analysis in combination with a BCR rebuilding approach, we show that this motif is required for the retention of unassembled Igα- or IgV molecules inside the endoplasmic reticulum and the binding of the Igα/Igβ heterodimer to the mIg molecule. We suggest that the BCR forms within the lipid bilayer of the membrane a symmetric Igα--mHC:mHC-IgV complex that is stabilized by an aromatic proline-tyrosine interaction. Outside the membrane this symmetric is broken by the disulfide-bridged dimerization of the extracellular Ig domains of Igα and IgV. However, symmetric of the receptor can be regained by a dimerization of two BCR complexes as suggested by the dissociation activation model.
The specific activation of B lymphocytes via the binding of antigen to their B cell antigen receptor (BCR) is of central importance for the establishment of humoral immunity and a successful vaccination. A better understanding of the antigen sensing process of B cells requires insight in the structure of the BCR comprising the mIg molecule and the Igα/IgV heterodimer in a 1:1 complex. How a symmetric molecule such as the mIg molecule is asymmetrically associated with only one Igα/Igβ heterodimer was a puzzle so far. We found that the transmembrane α-helices of Igα and Igβ share a conserved amino acid motif that is required for binding to the mIg molecule. We suggest that inside the lipid bilayer the BCR forms a symmetric Igα-mHC:mHC-IgV complex. According to our model complete BCR symmetry is established by receptor dimerization thus providing further evidence for the dissociation activation model (DAM). Our results give novel insight into the BCR structure and activation mechanism.
Keywords: B cell antigen receptor, assembly, symmetry