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Zhu,
Cheng
Zhu,
Cheng
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ItemFlow-enhanced adhesion regulated by a selectin interdomain hinge(Georgia Institute of Technology, 2006-09) Lou, Jizhong ; Yago, Tadayuki ; Klopocki, Arkadiusz G. ; Mehta, Padmaja ; Chen, Wei ; Zarnitsyna, Veronika I. ; Bovin, Nicolai V. ; Zhu, Cheng ; McEver, Rodger P.L-selectin requires a threshold shear to enable leukocytes to tether to and roll on vascular surfaces. Transport mechanisms govern flow-enhanced tethering, whereas force governs fl ow-enhanced rolling by prolonging the lifetimes of L-selectin–ligand complexes (catch bonds). Using selectin crystal structures, molecular dynamics simulations, site-directed mutagenesis, single-molecule force and kinetics experiments, Monte Carlo modeling, and flow chamber adhesion studies, we show that eliminating a hydrogen bond to increase the fl exibility of an interdomain hinge in L-selectin reduced the shear threshold for adhesion via two mechanisms. One affects the on-rate by increasing tethering through greater rotational diffusion. The other affects the off-rate by strengthening rolling through augmented catch bonds with longer lifetimes at smaller forces. By forcing open the hinge angle, ligand may slide across its interface with L-selectin to promote rebinding, thereby providing a mechanism for catch bonds. Thus, allosteric changes remote from the ligand-binding interface regulate both bond formation and dissociation.