TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility

William F. Hawse, Soumya De, Alex I. Greenwood, Linda K. Nicholson, Jaroslav Zajicek, Evgenii L. Kovrigin, David M Kranz, K. Christopher Garcia, Brian M. Baker

Research output: Contribution to journalArticle

Abstract

Although conformational changes in TCRs and peptide Ags presented by MHC protein (pMHC) molecules often occur upon binding, their relationship to intrinsic flexibility and role in ligand selectivity are poorly understood. In this study, we used nuclear magnetic resonance to study TCR-pMHC binding, examining recognition of the QL9/H-2Ld complex by the 2C TCR. Although the majority of the CDR loops of the 2C TCR rigidify upon binding, the CDR3b loop remains mobile within the TCR-pMHC interface. Remarkably, the region of the QL9 peptide that interfaces with CDR3b is also mobile in the free pMHC and in the TCR-pMHC complex. Determination of conformational exchange kinetics revealed that the motions of CDR3b and QL9 are closely matched. The matching of conformational exchange in the free proteins and its persistence in the complex enhances the thermodynamic and kinetic stability of the TCR-pMHC complex and provides a mechanism for facile binding. We thus propose that matching of structural fluctuations is a component of how TCRs scan among potential ligands for those that can bind with sufficient stability to enable T cell signaling. The Journal of Immunology, 2014, 192: 2885-2891.

Original languageEnglish (US)
Pages (from-to)2885-2891
Number of pages7
JournalJournal of Immunology
Volume192
Issue number6
DOIs
StatePublished - Mar 15 2014

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Ligands
Peptides
Allergy and Immunology
Thermodynamics
Proteins
Magnetic Resonance Spectroscopy
T-Lymphocytes
QL9 peptide

ASJC Scopus subject areas

  • Immunology

Cite this

Hawse, W. F., De, S., Greenwood, A. I., Nicholson, L. K., Zajicek, J., Kovrigin, E. L., ... Baker, B. M. (2014). TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility. Journal of Immunology, 192(6), 2885-2891. https://doi.org/10.4049/jimmunol.1302953

TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility. / Hawse, William F.; De, Soumya; Greenwood, Alex I.; Nicholson, Linda K.; Zajicek, Jaroslav; Kovrigin, Evgenii L.; Kranz, David M; Garcia, K. Christopher; Baker, Brian M.

In: Journal of Immunology, Vol. 192, No. 6, 15.03.2014, p. 2885-2891.

Research output: Contribution to journalArticle

Hawse, WF, De, S, Greenwood, AI, Nicholson, LK, Zajicek, J, Kovrigin, EL, Kranz, DM, Garcia, KC & Baker, BM 2014, 'TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility', Journal of Immunology, vol. 192, no. 6, pp. 2885-2891. https://doi.org/10.4049/jimmunol.1302953
Hawse, William F. ; De, Soumya ; Greenwood, Alex I. ; Nicholson, Linda K. ; Zajicek, Jaroslav ; Kovrigin, Evgenii L. ; Kranz, David M ; Garcia, K. Christopher ; Baker, Brian M. / TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility. In: Journal of Immunology. 2014 ; Vol. 192, No. 6. pp. 2885-2891.
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