LAUSR

Significance 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 into the structure of the BCR comprising the mIg molecule and the Igα/Igβ heterodimer in a 1:1 complex. How a symmetric molecule such as the mIg molecule is asymmetrically associated with only one Igα/Igβ heterodimer has been a puzzle. We suggest that inside the lipid bilayer the BCR forms a symmetric Igα-mHC:mHC-Igβ complex. Our results give insight into the BCR structure and the B cell activation mechanism. 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 Ig (mIg) molecule and the Igα/Igβ heterodimer functioning as antigen binding and signal transducing components, respectively. The mIg is a symmetric complex of 2 identical membrane-bound heavy chains (mHC) and 2 identical light chains. How the symmetric mIg molecule is asymmetrically associated with only one Igα/Igβ heterodimer has been a puzzle. Here we describe that Igα and Igβ 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 Igβ 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-Igβ complex that is stabilized by an aromatic proline-tyrosine interaction. Outside the membrane this symmetry is broken by the disulfide-bridged dimerization of the extracellular Ig domains of Igα and Igβ. However, symmetry of the receptor can be regained by a dimerization of 2 BCR complexes as suggested by the dissociation activation model.