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Force History Dependence of Receptor-Ligand Dissociation

Bryan T. Marshall ^*, Krishna K. Sarangapani , Jizhong Lou , Rodger P. McEver  and Cheng Zhu ^*  

^* Woodruff School of Mechanical Engineering, Coulter Department of Biomedical Engineering, and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332; and Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and Department of Biochemistry and Molecular Biology and Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Correspondence: Address reprint requests to Cheng Zhu, E-mail: cheng.zhu{at}me.gatech.edu.

Receptor-ligand bonds that mediate cell adhesion are often subjected to forces that regulate their dissociation via modulating off-rates. Off-rates control how long receptor-ligand bonds last and how much force they withstand. One should therefore be able to determine off-rates from either bond lifetime or unbinding force measurements. However, substantial discrepancies exist between the force dependence of off-rates derived from the two types of measurements even for the same interactions, e.g., selectins dissociating from their ligands, which mediate the tethering and rolling of leukocytes on vascular surfaces during inflammation and immune surveillance. We used atomic force microscopy to measure survival times of P-selectin dissociating from P-selectin glycoprotein ligand 1 or from an antibody in both bond lifetime and unbinding force experiments. By a new method of data analysis, we showed that the discrepancies resulted from the assumption that off-rates were functions of force only. The off-rates derived from forced dissociation data depended not only on force but also on the history of force application. This finding provides a new paradigm for understanding how force regulates receptor-ligand interactions.

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