Abstract
The adaptive immune system uses two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. While both proteins share a globally similar β-sandwich architecture, TCRs are specialized to recognize peptide antigens in the binding groove of the major histocompatibility complex, while antibodies can bind an almost infinite range of molecules. For both proteins, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3in TCRs and H3 in antibodies) is more structurally diverse. In this paper, we first update the definition of canonical forms in TCRs, build an auto-updating sequence-based prediction tool (available at http://opig.stats.ox.ac.uk/resources) and demonstrate its application on large scale sequencing studies. Given the global similarity of TCRs and antibodies, we then examine the structural similarity of their CDRs. We find that TCR and antibody CDRs tend to have different length distributions, and where they have similar lengths, they mostly occupy distinct structural spaces. In the rare cases where we found structural similarity, the underlying sequence patterns for the TCR and antibody version are different. Finally, where multiple structures have been solved for the same CDR sequence, the structural variability in TCR loops is higher than that in antibodies, suggesting TCR CDRs are more flexible. These structural differences between TCR and antibody CDRs may be important to their different biological functions.
Highlights
The adaptive immune system defends the host organism against a wide range of foreign molecules, or antigens, using two types of receptors: T-cell receptors (TCRs) and antibodies [1]
We have identified and refined the canonical class definitions of TCR complementarity-determining region (CDR) using a more up-to-date structural dataset, and used these to generate an auto-updating database and prediction server
In our dataset of 270 TCR structures, we find seven CDRα1, seven CDRα2, five CDRα3, one CDRβ1, and two CDRβ2 canonical classes
Summary
The adaptive immune system defends the host organism against a wide range of foreign molecules, or antigens, using two types of receptors: T-cell receptors (TCRs) and antibodies [1]. TCRs typically recognize peptide antigens presented via the major histocompatibility complex [MHC; [2]], while antibodies can bind almost any antigen, including proteins, peptides, and haptens [3] Despite their different roles in the immune response, these proteins share a β-sandwich fold (Figure 1) [4, 5]. TCRα and antibody light chains are made from the V and J genes, while TCRβ and antibody heavy chains are assembled from the V, D, and J genes, making the L-chain equivalent to α-chain and H-chain equivalent to β-chain [6, 8] In both types of Antigen Receptors CDR Loops Comparison antigen receptors, sequence, and structural diversity is concentrated in six hypervariable loops, known as the complementarity determining regions (CDRs). As the CDRs form the majority of the binding site, their conformations are critical to the binding
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