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Published 25 September 2006. doi:10.1083/jcb.200606056
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 7, 1107-1117
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Article

 Flow-enhanced adhesion regulated by a selectin interdomain hinge

Jizhong Lou3, Tadayuki Yago1, Arkadiusz G. Klopocki1, Padmaja Mehta1, Wei Chen5, Veronika I. Zarnitsyna5, Nicolai V. Bovin6, Cheng Zhu3,4,5, and Rodger P. McEver1,2

1 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
2 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
3 Institute for Bioengineering and Bioscience, 4 Coulter Department of Biomedical Engineering, and 5 Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
6 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

Correspondence to Rodger P. McEver: rodger-mcever{at}omrf.ouhsc.edu; or Cheng Zhu: cheng.zhu{at}me.gatech.edu

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.

J. Lou, T. Yago, and A.G. Klopocki contributed equally to this paper.

Abbreviations used in this paper: BFP, biomembrane force probe; HSA, human serum albumin; MD, molecular dynamics; PSGL, P-selectin glycoprotein ligand; RMSD, root mean square distance; sLex, sialyl Lewis x.


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