Allosteric role of the large-scale domain opening in biological catch-binding

Abstract

The proposed model demonstrates the allosteric role of the two-domain region of the receptor protein in the increased lifetimes of biological receptor/ligand bonds subjected to an external force. The interaction between the domains is represented by a bounded potential, containing two minima corresponding to the attached and separated conformations of the two protein domains. The dissociative potential with a single minimum describing receptor/ligand binding fluctuates between deep and shallow states, depending on whether the domains are attached or separated. A number of valuable analytic expressions are derived and are used to interpret experimental data for two catch bonds. The P-selectin/P-selectin-glycoprotein-ligand-1 (PSGL-1) bond is controlled by the interface between the epidermal growth factor (EGF) and lectin domains of P-selectin, and the type 1 fimbrial adhesive protein (FimH)/mannose bond is governed by the interface between the lectin and pilin domains of FimH. Catch-binding occurs in these systems when the external force stretches the receptor proteins and increases the interdomain distance. The allosteric effect is supported by independent measurements, in which the domains are kept separated by attachment of another ligand. The proposed model accurately describes the experimentally observed anomalous behavior of the lifetimes of the P-selectin/PSGL-1 and FimH/mannose complexes as a function of applied force and provides valuable insights into the mechanism of catch-binding.

Phenomenological and microscopic theories for catch bonds

“…The two-state model has been subsequently used to explain catch-slip data from a number of biological systems like the bacterial FimH adhesive protein (Thomas et al, 2006; Pereverzev et al, 2009), kinetochore-microtubule attachments (Akiyoshi et al, 2010), cell surface sulfatase and glycosaminoglycan interactions (Harder et al, 2015) and cadherin-catenin interactions (Buckley et al, 2014). Among all these experiments, the work by Akiyoshi et al on kinetochore-microtubule attachments (Akiyoshi et al, 2010) is a remarkable validation of the two-state model.…”

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.…”

Regulation of Catch Binding by Allosteric Transitions

“…11, and in Ref. 43. Further, the properties of function h ( f ) rationalize the rapid drop in the number of bonds surviving by time t , as discussed below.…”

“…As a result, the average lifetimes of the systems shown in Fig. 5 are well described using the following particularly simple expression $$\overline{\tau }(f)\approx [k_{12}(f)+k_{21}(f)]/[k_1(f)k_{21}(f)+k_2(f)k_{12}(f)]$$ that was used in our earlier work 43. The lines computed using Eq.…”

“…If the populations of the two states of the allosteric site rapidly reach equilibrium, this number can be reduced to 5, as in Ref. 43.…”