Abstract
Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug‐target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T‐cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T‐cell compartment. We have applied high‐pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide–HLA complexes. We find that different peptide sequences affect peptide–HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide‐binding interface, in a manner that could influence T‐cell antigen discrimination.
Highlights
The T-cell receptor (TCR), expressed on the surface of T cells, scans for antigens on the surface of virtually every cell in the body
We have previously reported a number of altered peptide ligands (APLs) for the 1E6 TCR using structural, biophysical and cellular analysis
We used cutting edge experimental approaches and molecular dynamics simulations to demonstrate that the peptide cargo is able to tune the conformational dynamics of Human leucocyte antigen (HLA)
Summary
The T-cell receptor (TCR), expressed on the surface of T cells, scans for antigens on the surface of virtually every cell in the body. For HLA class I, the peptide only accounts for ~ 2% of total amino acids in the pHLA class I molecule, its position within the binding groove ‘pins’ the entire complex together, that is HLA class I molecules do not generally form a stable structure without a bound peptide [8]. These peptides are edited by the antigen-processing machinery in the endoplasmic reticulum (ER) before being transported to the cell surface for TCR interrogation [9]. The co-receptors bind to an invariant site distal from the TCR, this interaction is known to play a role in TCR thymic selection [16], and can tune TCR cross-reactivity by altering T-cell potency [17,18]
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