The Molecular Basis of Triphasic Adhesion in E-selectins Anchoring Leukocytes Under Shear Flow*

One of the primary physiological roles of the selectin class of proteins is the anchoring of leukocytes to blood vessel walls by binding/unbinding with preferred ligands on leukocytes. This is crucial at sites of vascular injury and inflammation as a first line of defense or repair-and-control for the immune system. The hinge like structure of the selectin allows it to switch under shear forces between an extended and compact configuration, marked by differences in affinity for the ligand. This shows up as distinct regimes in the behaviour of the bond lifetime as a function of force: slip regimes where lifetimes decrease with force, and catch regimes where they counter-intuitively increase. E-selectin binding to the ligand PSGL-1 presents a particularly complex example of this- with a slip-catch-slip lifetime trend. We explain this triphasic behaviour using a diffusion-on-an-energy-landscape picture mapped to a three state bound-unbound system. By tying together force spectroscopy data and molecular mechanisms of force regulation in this complex along with robust structural corroboration of model parameters, our theory is the first to provide a detailed mechanistic basis for how such triphasic behaviour arises.