Regulation of Catch Bonds by Rate of Force Application

Abstract

The current paradigm for receptor-ligand dissociation kinetics assumes off-rates as functions of instantaneous force without impact from its prior history. This a priori assumption is the foundation for predicting dissociation from a given initial state using kinetic equations. Here we have invalidated this assumption by demonstrating the impact of force history with singlebond kinetic experiments involving selectins and their ligands that mediate leukocyte tethering and rolling on vascular surfaces during inflammation. Dissociation of bonds between L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) loaded at a constant ramp rate to a constant hold force behaved as catchslip bonds at low ramp rates that transformed to slip-only bonds at high ramp rates. Strikingly, bonds between L-selectin and 6-sulfo-sialyl Lewis X were impervious to ramp rate changes. This ligand-specific force history effect resembled the effect of a point mutation at the L-selectin surface (L-selectinA108H) predicted to contact the former but not the latter ligand, suggesting that the high ramp rate induced similar structural changes as the mutation. Although the A108H substitution in L-selectin eliminated the ramp rate responsiveness of its dissociation from PSGL-1, the inverse mutation H108A in P-selectin acquired the ramp rate responsiveness. Our data are well explained by the sliding-rebinding model for catch-slip bonds extended to incorporate the additional force history dependence, with Ala-108 playing a pivotal role in this structural mechanism. These results call for a paradigm shift in modeling the mechanical regulation of receptor-ligand bond dissociation, which includes conformational coupling between binding pocket and remote regions of the interacting molecules.Receptor-ligand interactions are usually modeled by chemical reaction kinetics wherein force-dependent kinetic rates are key parameters (1). A typical example is the interactions between selectins and their ligands that mediate the tethering and rolling of circulating leukocytes on vascular surfaces during their recruitment to secondary lymphoid organs or inflammation sites (1). L-selectin is expressed on leukocytes and binds to P-selectin glycoprotein ligand-1 (PSGL-1), 4 a leukocyte mucin, and to 6-sulfo-sialyl Lewis X (6-sulfo-sLe x ), a terminal component of glycans on a group of mucins expressed on endothelial cells in lymph nodes and some sites of inflammation (1). Selectin-ligand interactions provide adhesive forces for leukocytes to balance hemodynamic forces, and their kinetics have long been shown to depend on blood flow (2).Since first modeled by Bell (3) and later by many others (4 -11), the existing paradigm for the mechanical regulation of receptor-ligand dissociation assumes a priori that the kinetic rates depend only on the instantaneous, present level of force on the bond but not its prior history. A simple model is the first-order single-step irreversible dissociation of single monomeric bonds:where p is the probability of having a bond at time t. ...

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