Platelet glycoprotein Ibα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF

Abstract

Arterial blood flow enhances glycoprotein Ibα (GPIbα) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbα/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbα dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbα-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flowenhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbα on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.

Blood-clotting-inspired reversible polymer–colloid composite assembly in flow

“…As mentioned previously, the characteristic timescale for vWF tE10 À 4 s, which implies that we expect the binding energy to be in between the lowest binding energy we have studied here of 4 k B T and the intermediate energy of 5 k B T. Along the reaction coordinate, the distance between the binding minima and the top of the barrier for the GPIba-vWF A1 pair has been experimentally measured to be B2 nm 28 . This gives a bond breakup force of the order of B10 pN that is in excellent agreement with experiments 28,29 .…”

Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα

“…Nonequilibrium processes can be produced by mechanical perturbations such as force and flow. Indeed, a recent study has demonstrated that force slows off-rate of GPIb␣-VWF dissociation (an unusual characteristic called catch bonds), which underlies f lowenhanced platelet rolling on VWF and prevents platelet agglutination (21). GOF mutations in the A1 domain away from the binding site eliminate catch bonds, abolish the flow requirement for rolling, and cause platelet agglutination.…”

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

“…Surprisingly, we find a complex mechanical regulation of adhesive bonds at the single-molecule level: tensile force prolongs the bond lifetime (that is, catch bonds). In contrast to the well-known catch bonds of bimolecular systems, such as cell adhesion receptors (integrins 28,38,39 , selectins 40,41 , glycoprotein Iba 30,42 , E-cadherin 43 and FimH 44 ), the T-cell receptor 31 and cytoskeletal linkages 45,46 , the Thy-1 catch bond is strongly correlated with a bond-stiffening phenotype, termed 'dynamic catch', which partially shifts force to the already engaged but unstretched coreceptor Syn4. Thus, the data reveal a unique, previously unreported class of receptor-ligand bonds whereby force tightens co-receptor engagement that is required for forcemediated adhesion signalling.…”