Flow-enhanced adhesion regulated by a selectin interdomain hinge

• Authors: Jizhong Lou, Georgia Institute of Technology; Tadayuki Yago, Oklahoma Medical Research Foundation; Arkadiusz G. Klopocki, Oklahoma Medical Research Foundation; Padmaja Mehta, Oklahoma Medical Research Foundation; Wei Chen, Georgia Institute of Technology; Veronika Zarnitsyna, Emory University; Nicolai V. Bovin, Russian Academy of Sciences; Cheng Zhu, Emory University; Rodger P. McEver, Oklahoma Medical Research Foundation
• Journal Title: JOURNAL OF CELL BIOLOGY
• Volume: Volume 174, Number 7
• Publisher: ROCKEFELLER UNIV PRESS | 2006-09-25, Pages 1107-1117
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1083/jcb.200606056
• Subjects: Biology, Cell
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; VON-WILLEBRAND-FACTOR; P-SELECTIN; GLYCOPROTEIN LIGAND-1; CATCH BONDS; MOLECULAR-DYNAMICS; BACTERIAL ADHESION; CELL-ADHESION; SHEAR; BINDING; FORCE

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.