U.S. flag

An official website of the United States government

Dot gov

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Https

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

PubAg

Main content area

Peptide cargo tunes a network of correlated motions in human leucocyte antigens

Author:
Jade R. Hopkins, Rory M. Crean, Dragana A. M. Catici, Andrew K. Sewell, Vickery L. Arcus, Marc W. Van der Kamp, David K. Cole, Christopher R. Pudney
Source:
FEBS journal 2020 v.287 no.17 pp. 3777-3793
ISSN:
1742-464X
Subject:
T-lymphocytes, adaptive immunity, antigens, humans, immune response, molecular dynamics, peptides
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.
Agid:
7096066