YIA Session (15 min) The 48th Lorne Conference on Protein Structure and Function 2023

T-cell and B-cell antigen receptors share a conserved core transmembrane structure (#17)

Samyuktha Ramesh 1 2 , Soohyung Park 3 , Wonpil Im 3 , Melissa J Call 1 2 , Matthew E Call 1 2
  1. Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Biological Sciences and Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania, USA

Antigen receptors on B and T lymphocytes (BCRs and TCRs) share a common architecture in which variable dimeric antigen-binding modules assemble with invariant dimeric signaling modules to form functional receptor complexes1. In the TCR, a highly conserved TCRαβ transmembrane (TM) interface forms a rigid structure2 around which its three dimeric signaling modules assemble through well-characterized polar interactions3. Noting that the key features stabilizing this TCRαβ TM interface also appear with high evolutionary conservation in the TM sequences of the membrane immunoglobulin (mIg) heavy chains that form the BCR’s homodimeric antigen-binding module, we asked whether the BCR contained an analogous TM structure. Using an unbiased biochemical and computational modelling approach, we found that the mouse IgM BCR forms a core TM structure that is remarkably similar to that of the TCR. We performed cysteine-crosslinking on BCRs assembled in endoplasmic reticulum microsomes in an in vitro translation and assembly system. This data was then used to restrain molecular dynamics simulations performed in lipid bilayers to generate the model of the BCR mIg TM domain. This structure is reinforced by a network of inter-helical hydrogen bonds, and our model is nearly identical to the arrangement observed in the just-released cryo-EM structures of intact human BCRs4,5. Our biochemical analysis shows that the integrity of this TM structure is vital for stable assembly with the BCR signaling module CD79AB in the B cell endoplasmic reticulum, and molecular dynamics simulations indicate that BCRs of all five isotypes can form comparable structures. These results demonstrate that, despite their many differences in composition, complexity and ligand type, TCRs and BCRs rely on a common core TM structure that has been shaped by evolution for optimal receptor assembly and stability in the cell membrane.

This work has been accepted for publication in The Proceedings of the National Academy of Sciences (PNAS) and is currently in press.

  1. R. Berry, M. E. Call, Modular Activating Receptors in Innate and Adaptive Immunity. Biochemistry 56, 1383-1402 (2017).
  2. L. Krshnan, S. Park, W. Im, M. J. Call, M. E. Call, A conserved alphabeta transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane. Proc Natl Acad Sci U S A 113, E6649-E6658 (2016).
  3. M. E. Call, J. Pyrdol, M. Wiedmann, K. W. Wucherpfennig, The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 111, 967-979 (2002).
  4. X. Ma et al., Cryo-EM structures of two human B cell receptor isotypes. Science (New York, N.Y.) 377, 880-885 (2022).
  5. Q. Su et al., Cryo-EM structure of the human IgM B cell receptor. Science (New York, N.Y.) 377, 875-880 (2022).