T cell receptor recognition via cooperative conformational plasticity
Susan J Gagnon1, Oleg Y Borbulevych, Rebecca L Davis-Harrison
1Molecular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Molecular Biology
|September 12, 2006
Summary
T cell receptor (TCR) cross-reactivity allows recognition of diverse ligands. Structural analysis reveals cooperative conformational plasticity in TCR-ligand binding, involving dynamic changes in TCR and peptide interfaces.
Area of Science:
- Immunology
- Structural Biology
- Molecular Mechanisms
Background:
- T cell receptor (TCR) cross-reactivity is crucial for immunity and autoimmunity.
- The molecular basis of TCR recognition of diverse ligands remains incompletely understood.
Purpose of the Study:
- To investigate the cross-reactive recognition mechanism of the human T cell lymphotropic virus-1 (HTLV-1) Tax-specific TCR A6.
- To analyze the structural basis of TCR recognition of haptenated peptides.
Main Methods:
- Examined the response of the A6 TCR to a panel of haptenated peptides derived from HTLV-1 Tax.
- Determined crystal structures of the Tax5K-IBA peptide complexed with HLA-A*0201, both free and bound to the A6 TCR.
Main Results:
- The A6 TCR demonstrated cross-reactivity towards the haptenated peptide Tax-5K-4-(3-Indolyl)-butyric acid (IBA).
- Crystal structures revealed cooperative conformational plasticity at the TCR-peptide-MHC interface.
- Conformational changes occurred in TCR complementarity determining region (CDR) loops, Valpha/Vbeta domains, and the modified peptide.
Conclusions:
- TCR cross-reactivity involves complex molecular mechanisms beyond simple mimicry or CDR shifts.
- Cooperative conformational plasticity is a key mechanism enabling TCRs to recognize diverse ligands.
- Protein dynamics play a significant role in the intricate process of T cell receptor recognition.
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