title: Flow-enhanced adhesion regulated by a selectin interdomain hinge.
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 flow-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 flexibility 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.
authors.affiliation: Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Yago
authors.forename: Arkadiusz G
authors.initials: AG
authors.lastname: Klopocki
authors.forename: Padmaja
authors.initials: P
authors.lastname: Mehta
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Veronika I
authors.initials: VI
authors.lastname: Zarnitsyna
authors.forename: Nicolai V
authors.initials: NV
authors.lastname: Bovin
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
mesh_terms: D002448:Cell Adhesion; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D008024:Ligands; D008954:Models, Biological; D008968:Molecular Conformation; D009010:Monte Carlo Method; D033081:Shear Strength
chemical_list: D008024:Ligands; D019041:L-Selectin