Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning - PubMed (original) (raw)

Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning

J J Boniface et al. Proc Natl Acad Sci U S A. 1999.

Abstract

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.

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Figures

Figure 1

Figure 1

Binding of 2B4 to MCC–Ek monitored at different temperatures on a BIAcore device. Injection of TCR (0.45 mg/ml) was from ≈70 to ≈160 sec, after which dissociation was initiated. Each curve in A (20–37°C) can be distinguished by the faster approach to equilibrium at higher temperatures. Binding curves in A are not directly comparable to those in B (10–20°C), because they were obtained in separate experiments, on different instruments, and at slightly different densities of immobilized ligand. RU, resonance units.

Figure 2

Figure 2

Temperature dependence of 2B4–MCC–Ek association-rate (A) and dissociation-rate (B) constants. (Inset) Variation of the reaction half-life with temperature. Data points shown represent the mean value of three to seven independent measurements with at least three different analyte concentrations. Error bars represent SEM; uncertainty involved in temperature setting was ±0.1°C. Data were fit to a rearranged form of Eq. 1 (detailed in Materials and Methods) with a reference temperature _T_0 of 298.15 K. Note, we chose to illustrate the data by using temperature on the x axis, as opposed to the reciprocal of temperature that is common to Van’t Hoff analysis.

Figure 3

Figure 3

The thermodynamics of the 2B4–MCC–Ek association. (A) Δ_G_°assoc data were fit to Eq. 1 (T_0 = 298.15 K) to yield the parameters and the best-fit line shown. Errors for the indicated parameters represent the estimated SEM obtained from data fitting. (B) Δ_H° and T_Δ_S° values were derived from Eqs. 2 and 3 detailed in Materials and Methods.

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