title: TCR scanning of peptide/MHC through complementary matching of receptor and ligand molecular flexibility.
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-2L(d) complex by the 2C TCR. Although the majority of the CDR loops of the 2C TCR rigidify upon binding, the CDR3β loop remains mobile within the TCR-pMHC interface. Remarkably, the region of the QL9 peptide that interfaces with CDR3β is also mobile in the free pMHC and in the TCR-pMHC complex. Determination of conformational exchange kinetics revealed that the motions of CDR3β 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.
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
authors: William F
authors: WF
authors: Hawse
authors: Soumya
authors: S
authors: De
authors: Alex I
authors: AI
authors: Greenwood
authors: Linda K
authors: LK
authors: Nicholson
authors: Jaroslav
authors: J
authors: Zajicek
authors: Evgenii L
authors: EL
authors: Kovrigin
authors: David M
authors: DM
authors: Kranz
authors: K Christopher
authors: KC
authors: Garcia
authors: Brian M
authors: BM
authors: Baker
mesh_terms: D000818:Animals; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D022801:Complementarity Determining Regions; D008024:Ligands; D009842:Oligopeptides; C440022:QL9 peptide; D011948:Receptors, Antigen, T-Cell