The Energetic Landscape of Catch Bonds in TCR Interfaces

Abstract

Recognition of peptide/MHC complexes by αβ TCRs has traditionally been viewed through the lens of conventional receptor-ligand theory. Recent work, however, has shown that TCR recognition and T cell signaling can be profoundly influenced and tuned by mechanical forces. One outcome of applied force is the catch bond, where TCR dissociation rates decrease (half-lives increase) when limited force is applied. Although catch bond behavior is believed to be widespread in biology, its counterintuitive nature coupled with the difficulties of describing mechanisms at the structural level have resulted in considerable mystique. In this review, we demonstrate that viewing catch bonds through the lens of energy landscapes, barriers, and the ensuing reaction rates can help demystify catch bonding and provide a foundation on which atomic-level TCR catch bond mechanisms can be built.

Figure 1.

Schematics of force induced changes to the TCR binding energy landscape. A) Simplified energy diagram showing how a slower rate of dissociation can emerge through force-induced alteration of the height of the energy barrier for dissociation. Free energy is on the y-axis, dimensionless reaction coordinate is on the x-axis. The blue line represents the traditional, force-free binding reaction, showing a single binding transition state as the unbound TCR and pMHC associate to form the lower energy TCR-pMHC complex. The solid green line illustrates force-induced stabilization of the complex, resulting in a slower dissociation rate due to the higher barrier. Although the solid green line emphasizes stabilization of the bound state, force-induced impacts to the entire trajectory are possible as illustrated by the broader, semi-transparent green shading around the line beginning just before the transition state. Potential new states introduced with applied force are not shown. B) Energy landscape figure that more comprehensively illustrates force-induced stabilization of the TCR-pMHC complex. In the absence of force, TCR binds pMHC forming the force-free TCR-pMHC complex as illustrated by the blue path. With the application of weak force, the TCR-pMHC complex can transition to an altered conformation, referred to as TCR-pMHC*, illustrated by the red path. Compared to the force-free complex, this force-stabilized conformation has a higher barrier for dissociation and thus does so with a slower rate, as shown by the green line (mimicking the green line in panel A; note that dissociation by first returning to the force-free complex is also possible but will be even slower, as there two barriers to cross). As described in the text, the figure is still simplified, showing a substantially stabilized complex for effect and leaving out possible microstates or intermediates and other consequences such as force-induced alterations of barrier heights as shown in panel A. C) In the absence of applied force, the TCR-pMHC* complex in panel B cannot form to any appreciable extent as its energy is high. The energy surface in this panel can also describe a force-induced slip bond, in which applied force pulls the complex into a destabilized state from which dissociation is rapid.