Abstract
Complementarity determining region (CDR) loop flexibility has been suggested to play an important role in the selection and binding of ligands by T cell receptors (TCRs) of the cellular immune system. However, questions remain regarding the role of loop motion in TCR binding, and crystallographic structures have raised questions about the extent to which generalizations can be made. Here we studied the flexibility of two structurally well characterized αβ TCRs, A6 and DMF5. We found that the two receptors utilize loop motion very differently in ligand binding and cross-reactivity. While the loops of A6 move rapidly in an uncorrelated fashion, those of DMF5 are substantially less mobile. Accordingly, the mechanisms of binding and cross-reactivity are very different between the two TCRs: whereas A6 relies on conformational selection to select and bind different ligands, DMF5 uses a more rigid, permissive architecture with greater reliance on slower motions or induced-fit. In addition to binding site flexibility, we also explored whether ligand-binding resulted in common dynamical changes in A6 and DMF5 that could contribute to TCR triggering. Although binding-linked motional changes propagated throughout both receptors, no common features were observed, suggesting that changes in nanosecond-level TCR structural dynamics do not contribute to T cell signaling.
Highlights
Described by a conformational selection rather than induced-fit mechanism[21]
The complementarity determining region (CDR) loops of the DMF5 T cell receptor are less mobile than those of A6
Some progress has been made using fluorescence and NMR18,20,25,34, due to the technical challenges presented by recombinant T cell receptor (TCR) and TCR-pMHC complexes, insight in the near future is likely to emerge from computational studies[35]
Summary
Described by a conformational selection rather than induced-fit mechanism[21]. The relevance of this data was further demonstrated by the rational design of high affinity A6 TCR variants through the introduction of mutations that limited CDR3β loop motion[22]. To broaden our understanding of the motional properties of TCRs and how these influence ligand binding and selection, here we compared the dynamics of the α β TCR A6 with those of another structurally well-characterized TCR, DMF513. Our results expand our understanding of how motion impacts TCR binding, ligand selection, and cross-reactivity, and provide a point for further studies of how binding-linked changes might contribute to T cell signaling. They indicate that simplifying generalizations about the role of flexibility in TCR functional properties cannot be made, and provide data for how motion may be accounted for in efforts to manipulate TCR binding
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