Dynamics of unbinding of cell adhesion molecules: Transition from catch to slip bonds

Abstract

The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for the specific P-selectin-P-selectin glycoprotein ligand (sPSGL-1) the average bond lifetime ͗t͘ initially increases (catch bonds) at low (<10 pN) constant force, f, and decreases when f > 10 pN (slip bonds). In contrast, for the complex with G1 anti-P-selectin monoclonal antibody ͗t͘ monotonically decreases with f. To quantitatively map the energy landscape of such complexes we use a model that considers the possibility of redistribution of population from one force-free state to another force-stabilized bound state. The excellent agreement between theory and experiments allows us to extract energy landscape parameters by fitting the calculated curves to the lifetime measurements for both sPSGL-1 and G1. Surprisingly, the unbinding transition state for P-selectin-G1 complex is close (0.32 nm) to the bound state, implying that the interaction is brittle, i.e., once deformed, the complex fractures. In contrast, the unbinding transition state of the P-selectin-sPSGL-1 complex is far (Ϸ 1.5 nm) from the bound state, indicative of a compliant structure. Constant f energy landscape parameters are used to compute the distributions of unbinding times and unbinding forces as a function of the loading rate, rf. For a given rf, unbinding of sPSGL-1 occurs over a broader range of f with the most probable f being an order of magnitude less than for G1. The theory for cell adhesion complexes can be used to predict the outcomes of unbinding of other protein-protein complexes. F ormation and breakage of noncovalent protein-protein interactions are crucial in the functions of cell-adhesion complexes. Adhesive interactions between leukocytes and blood vessel walls involve a dynamic competition between bond formation and breakage (1). Under physiological conditions of blood circulation, the hydrodynamic force of the flow is applied to the linkage between leukocytes and endothelium. Rolling of cells requires transient tethering of the cell to the substrate and subsequent dissociation at high shear rates that are generated by the hydrodynamic flow field. Because of the requirement of adhesive interaction and the breakage of such bonds to facilitate rolling, only a certain class of molecules is involved in the recognition process. The remarkable rolling function is mediated by Ca 2ϩ -dependent specific bonds between the family of L-, E-, and P-selectin receptors and their specific ligands such as ESL-1, podocalyxin, and PSGL-1 (2-6). Specific interactions of Pselectins, expressed in endothelial cells or platelets, with PSGL-1 (P-selectin glycoprotein ligand 1) enable leukocytes to roll on vascular surfaces during the inflammatory response by transient interruption of cell transport (tethering) in blood flow under constant wall shear stress. These interactions have been used extensively to probe tethering and rolling of leukocytes on vascular surfaces in flow channel experiments...

Resolving the molecular mechanism of cadherin catch bond formation

“…These include energy landscapes with one bound state and two unbinding pathways 43 ; an energy landscape with two bound states, one of which is preferentially stabilized by force 44,45 ; bond dissociation along a multidimensional landscape where the direction of the tensile force and the reaction coordinate are misaligned [46][47][48] ; a freeenergy landscape with dynamic disorder that thermally fluctuates with time 49,50 ; and allosteric deformation models where external force changes the structure of the receptor either directly at the ligand-binding site 51 or at a distal location that ultimately propagates the deformation to the binding pocket [52][53][54][55] . Our simulations suggest that X-dimers form catch bonds via a slidingrebinding mechanism where a pulling force flexes the ectodomain and slides opposing EC1 domains resulting in the formation of de novo, force-induced H-bonds.…”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…The tyrosine phosphorylation of the FA proteins CAS pY‐165, FAK pY‐925, and paxillin pY‐118 causes FA remodeling,20, 50, 51 which we previously found to occur through an endocytic recycling pathway, allowing cyclic remodeling of the FAs. The mechanisms that trigger the growth or degradation of individual FAs in the intact aorta are controversial, but the previously described concept of “slip” and “catch” bond formation at high versus low forces, respectively,52 may apply. Perhaps during the high forces of systole, some focal adhesion proteins break loose from the FA and enter into endosomal recycling pathways, allowing compliance and expansion of the aorta, but during lower, diastolic, forces, the FA surface rebuilds, promoting the return to the diastolic aortic diameter.…”

Deformation Model for Thioredoxin Catalysis of Disulfide Bond Dissociation by Force

“…We would like to emphasize that the description of the catch-slip anomaly proposed in the current work is not unique, and that several alternative models are available in the literature. 2,8,16,21,26,31 The current model differs from the alternative interpretations by its mathematical simplicity and by the bond deformation concept that is used to rationalize the physics of catchbinding.…”

“…It will be introduced below following the analysis of the general solution of Eq. (2). Considering that initially, at t = 0 the probabilities are equal to p 0 (0) = 1, p 1 (0) = 0, and p 2 (0) = 0, the solution of Eq.…”

“…The catch-slip binding transitions were discovered recently in a number of receptor-ligand biological complexes. 2,3,7,8,10,17,18,[21][22][23][24]26,27,32 The disulfide bond presents the first example of a chemical catch-bond, i.e., a system in which the increased lifetimes are associated with breaking a covalent bond.…”