Flow-enhanced adhesion regulated by a selectin interdomain hinge

• Published in: The Journal of cell biology 2006-09, Vol.174 (7), p.1107-1117
• Main Authors: Lou, Jizhong, Yago, Tadayuki, Klopocki, Arkadiusz G, Mehta, Padmaja, Chen, Wei, Zarnitsyna, Veronika I, Bovin, Nicolai V, Zhu, Cheng, McEver, Rodger P
• Format: Article
• Language: English
• Subjects: Adhesive bonding; Binding sites; Cell Adhesion; Cell adhesion & migration; Chemical bonding; Crystal structure; Diffusion coefficient; Glycoproteins; Humans; Hydrogen bonds; L-Selectin - metabolism; Lectins; Leukocyte Rolling - physiology; Leukocytes; Leukocytes - physiology; Ligands; Models, Biological; Molecular biology; Molecular Conformation; Monte Carlo Method; Neutrophils; Selectins; Shear Strength
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200606056

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.