Title:
Flow-enhanced adhesion regulated by a selectin interdomain hinge
Flow-enhanced adhesion regulated by a selectin interdomain hinge
Author(s)
Lou, Jizhong
Yago, Tadayuki
Klopocki, Arkadiusz G.
Mehta, Padmaja
Chen, Wei
Zarnitsyna, Veronika I.
Bovin, Nicolai V.
Zhu, Cheng
McEver, Rodger P.
Yago, Tadayuki
Klopocki, Arkadiusz G.
Mehta, Padmaja
Chen, Wei
Zarnitsyna, Veronika I.
Bovin, Nicolai V.
Zhu, Cheng
McEver, Rodger P.
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Abstract
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.
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2006-09
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Article