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Previously Hidden Dynamics at the TCR-Peptide-MHC Interface Revealed
James Fodor1, Blake T Riley1, Natalie A Borg2
1Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Journal of Immunology (Baltimore, Md. : 1950)
|May 6, 2018
Summary
Ensemble refinement of X-ray crystallography data reveals hidden conformational dynamics in T cell receptor-peptide-MHC interactions. This advanced analysis enhances understanding of adaptive immunity, disease associations, and vaccine design beyond static structural views.
Area of Science:
- Structural biology
- Immunology
- Biophysics
Background:
- Understanding adaptive T cell immunity relies on characterizing alpha-beta T cell receptor (αβ TCR) and peptide-MHC (pMHC) interactions.
- X-ray crystallography typically provides static snapshots, potentially missing crucial dynamic information relevant to protein function.
Purpose of the Study:
- To investigate conformational dynamics in pMHC complexes using ensemble refinement of existing crystallographic data.
- To reveal previously hidden dynamic information and enhance functional interpretations of TCR-pMHC interactions.
Main Methods:
- Interrogation of 309 crystallographic structures of pMHC complexes.
- Application of ensemble refinement techniques to extract dynamic information from X-ray data.
- Focus on a subset of human pMHC class I systems.
Main Results:
- Ensemble methods uncovered significant conformational plasticity in many human pMHC class I systems.
- Revealed additional dynamic information not apparent from single static structures.
- Provided insights into disease associations (HLA subtypes), peptide presentation, vaccine design, and TCR binding models (induced fit vs. conformational selection).
Conclusions:
- Single-structure analysis of pMHC interactions overlooks accessible dynamic information in X-ray data.
- Ensemble methods enrich the interpretation of existing structural data by revealing alternative protein conformations.
- This approach provides crucial missing information on the dynamics of characterized TCR-pMHC interactions.
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