Regulation of Catch Bonds by Rate of Force Application

• Published in: The Journal of biological chemistry Vol. 286; no. 37; pp. 32749 - 32761
• Main Authors: Sarangapani, Krishna K., Qian, Jin, Chen, Wei, Zarnitsyna, Veronika I., Mehta, Padmaja, Yago, Tadayuki, McEver, Rodger P., Zhu, Cheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.09.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Substitution; Atomic Force Microscopy; Biophysics; Catch Bonds; Cell Adhesion; Force History; Glycoprotein; Humans; Inflammation; L-Selectin - chemistry; L-Selectin - metabolism; Lewis X Antigen - chemistry; Lewis X Antigen - metabolism; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Models, Chemical; Molecular Biophysics; Mutation, Missense; Protein Binding; Ramp Rate; Selectins; Structure-Activity Relationship; Ramp Rate; Catch Bonds; Glycoprotein; Selectins; Force History; Inflammation; Atomic Force Microscopy; Biophysics; Cell Adhesion
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.240044

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 single-bond 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 catch-slip 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.