Flow-enhanced adhesion regulated by a selectin interdomain hinge.
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.
Lou
Jizhong
J
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Yago
Tadayuki
T
Klopocki
Arkadiusz G
AG
Mehta
Padmaja
P
Chen
Wei
W
Zarnitsyna
Veronika I
VI
Bovin
Nicolai V
NV
Zhu
Cheng
C
McEver
Rodger P
RP
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
D008024:Ligands; D019041:L-Selectin