Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning.
Antigen-dependent activation of T lymphocytes requires T cell receptor (TCR)-mediated recognition of specific peptides, together with the MHC molecules to which they are bound. To achieve this recognition in a reasonable time frame, the TCR must scan and discriminate rapidly between thousands of MHC molecules differing from each other only in their bound peptides. Kinetic analysis of the interaction between a TCR and its cognate peptide-MHC complex indicates that both association and dissociation depend heavily on the temperature, indicating the presence of large energy barriers in both phases. Thermodynamic analysis reveals changes in heat capacity and entropy that are characteristic of protein-ligand associations in which local folding is coupled to binding. Such an "induced-fit" mechanism is characteristic of sequence-specific DNA-binding proteins that must also recognize specific ligands in the presence of a high background of competing elements. Here, we propose that induced fit may endow the TCR with its requisite discriminatory capacity and suggest a model whereby the loosely structured antigen-binding loops of the TCR rapidly explore peptide-MHC complexes on the cell surface until some critical structural complementarity is achieved through localized folding transitions. We further suggest that conformational changes, implicit in this model, may also propagate beyond the TCR antigen-binding site and directly affect self-association of ligated TCRs or TCR-CD3 interactions required for signaling.
Boniface
J J
JJ
Department of Microbiology, Stanford University School of Medicine, Stanford, CA 94305-5402, USA.
Reich
Z
Z
Lyons
D S
DS
Davis
M M
MM
D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013816:Thermodynamics
D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D004247:DNA