A symmetric geometry of transmembrane domains inside the B cell antigen receptor complex

Abstract

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.

Presence of Natural Killer B Cells in Simian Immunodeficiency Virus-Infected Colon That Have Properties and Functions Similar to Those of Natural Killer Cells and B Cells but Are a Distinct Cell Population

“…Moreover, the association of CD79b with the α heavy Ig chain ( Fig. 3E ) essentially rules out any role for a poly-IgA receptor on NKB cells leading to monomeric IgA surface expression ( 34 , 35 ). Although CD79a is also expressed, staining was limited and likely a consequence of using a monoclonal antibody to a human epitope that may not be optimal for macaque antigen ( Fig.…”

“…This finding suggests that the skewing of NKB cell light chains is more similar to that of mucosal plasma cells ( 32 ) than that of peripheral blood B cells, which have a greater predominance of κ light chains ( 33 ). Since surface Ig expression is dependent on Ig heavy chain interaction with CD79 ( 34 , 35 ), we stained for CD79b expression. CD79b expression was associated with anti-IgA surface expression on NKB cells but not B cells ( Fig.…”

Structural principles of B-cell antigen receptor assembly

“…For TCR, charged interactions deep within the TMD helices are critical for its assembly 10 . For BCR, the evolutionary conserved E/Q-X 10 -P motifs in Igα (E142-X 10 -P153) and Igβ (Q164-X10-P175) and the YS motifs (Y466-S467) in mIg define certain polar interactions within the membrane, albeit also asymmetrically instead of symmetrically as predicted 24,25,26,27 . The TCRα/µ incorporates three CD3 signalling dimers and thus forms an 8-helix bundle in the TCR TMD, with the α/β helices surrounded by helices of the CD3 components.…”

“…A previous analysis of mIg TMD sequences suggested that the side of the α-helix highly conserved in all mIg isotypes (TM-C) associates with TMDs of the Igα/β heterodimer, whereas the other side harbouring class-specific residues (TM-S) is involved in µHC dimerization and mIg oligomerization 24 . Our cryo-EM structure shows that this assignment is not correct as the central TM-C side mediates µHC dimerization and its neighbouring residues dominantly interact with Igα TMD and to a lesser extent Igβ TMD.…”

Discovery of a Novel MHC Class I Lineage in Teleost Fish which Shows Unprecedented Levels of Ectodomain Deterioration while Possessing an Impressive Cytoplasmic Tail Motif

“…Equally, the conservation of a hydrophilic serine at position 304 in the teleost H lineage transmembrane domain sequences, and maybe also the partial conservation of a proline at position 290, suggest interaction of the TM domain with some other molecule. Examples of molecules believed to use a conserved serine/threonine or proline within the transmembrane domain for intermolecular protein binding are CD74 [54,55] and Igα [56], respectively. The identity of the molecules putatively interacting with the HAA TM/CY regions can only be guessed.…”