title: 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 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.
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Sarangapani
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Veronika I
authors.initials: VI
authors.lastname: Zarnitsyna
authors.forename: Padmaja
authors.initials: P
authors.lastname: Mehta
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Yago
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D019943:Amino Acid Substitution; D006801:Humans; D019041:L-Selectin / Q000737:chemistry* / Q000378:metabolism; D016256:Lewis X Antigen / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008956:Models, Chemical; D020125:Mutation, Missense; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D016256:Lewis X Antigen; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D019041:L-Selectin