Kinetic proofreading and the search for nonself-peptides

Accumulation of Serial Forces on TCR and CD8 Frequently Applied by Agonist Antigenic Peptides Embedded in MHC Molecules Triggers Calcium in T Cells

“…Our data demonstrate that, under our experimental conditions, the series of reaction steps of the signaling cascade required for calcium induction in T cells can be triggered but must be sustained by different TCRs rapidly forming and breaking bonds with agonist pMHC (with or without concurrent binding and unbinding with CD8) in a sequential manner. This emphasizes the importance of both on- and off-rates, supporting a recently extended version of the kinetic proofreading model (39, 40). The transient, intermittent, reversible, and cumulative nature of T-cell triggering indicates that intermediate signaling states would persist when the TCR–pMHC bonds dissociate and the proofreading steps would resume upon their rebinding, as proposed by the kinetic proofreading model (39, 40) and recently extended version of the serial engagement model (7).…”

“…This emphasizes the importance of both on- and off-rates, supporting a recently extended version of the kinetic proofreading model (39, 40). The transient, intermittent, reversible, and cumulative nature of T-cell triggering indicates that intermediate signaling states would persist when the TCR–pMHC bonds dissociate and the proofreading steps would resume upon their rebinding, as proposed by the kinetic proofreading model (39, 40) and recently extended version of the serial engagement model (7). Our data suggest that the concentrations of signaling intermediates may represent the intermediate signaling states, which have to be built up progressively by sequential engagements of different TCRs.…”

Accumulation of Dynamic Catch Bonds between TCR and Agonist Peptide-MHC Triggers T Cell Signaling

“…The original model has subsequently been refined and extended to accommodate new experimental results (Dushek et al, 2009; Jansson, 2011). One recent extension allows the intermediate signaling states to persist when the pMHC dissociates and the proofreading steps to resume upon pMHC rebinding, thus incorporating the TCR–pMHC on-rate as another important parameter to the model (Dushek et al, 2009).…”

Differences in affinities between the homologous and the heterologous rabbit prolactin–receptor interaction with respect to proliferation and differentiation activities

“…In this context, rbPRL may amplify the response by sequentially triggering multiple receptors, by virtue of its lower binding affinity as a consequence of its higher dissociation rate. Thus, increased re-binding may compensate for low affinity in the differentiation assay, a situation reminiscent of the TCR (Jansson, 2011).…”