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Paper36-Force-mediated-kinetics-P-selectin-ligand-AFM-PNAS-95-12283-Fritz-et-al(1998)

Paper36-Force-mediated-kinetics-P-selectin-ligand-AFM-PNAS-95-12283-Fritz-et-al(1998)

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Proc. Natl. Acad. Sci. USA Vol. 95, pp. 12283–12288, October 1998 Biophysics Force-mediated kinetics of single P-selectin y ligand complexes observed by atomic force microscopy J U ¨ RGEN F RITZ * ² , A NDREAS G. K ATOPODIS , F RANK K OLBINGER , AND D ARIO A NSELMETTI * § *Novartis Services AG, Scientific Services, Physics, WKL-127.620, CH-4002 Basel, Switzerland; Novartis Pharma AG, Transplantation Preclinical Research, WSJ-386.645, CH-4002 Basel, Switzerland; and ² University of Basel, Institute of Physics, Klingelbergstrasse 82, CH-4056 Basel, Switzerland Communicated by Calvin F. Quate, Stanford University, Stanford, CA, August 18, 1998 (received for review May 24, 1998) ABSTRACT Leukocytes roll along the endothelium of postcapillary venules in response to inflammatory signals. Rolling under the hydrodynamic drag forces of blood flow is mediated by the interaction between selectins and their li- gands across the leukocyte and endothelial cell surfaces. Here we present force-spectroscopy experiments on single com- plexes of P-selectin and P-selectin glycoprotein ligand-1 by atomic force microscopy to determine the intrinsic molecular properties of this dynamic adhesion process. By modeling intermolecular and intramolecular forces as well as the ad- hesion probability in atomic force microscopy experiments we gain information on rupture forces, elasticity, and kinetics of the P-selectin y P-selectin glycoprotein ligand-1 interaction. The complexes are able to withstand forces up to 165 pN and show a chain-like elasticity with a molecular spring constant of 5.3 pN nm 2 1 and a persistence length of 0.35 nm. The dissociation constant (off-rate) varies over three orders of magnitude from 0.02 s 2 1 under zero force up to 15 s 2 1 under external applied forces. Rupture force and lifetime of the complexes are not constant, but directly depend on the applied force per unit time, which is a product of the intrinsic molecular elasticity and the external pulling velocity. The high strength of binding combined with force-dependent rate con- stants and high molecular elasticity are tailored to support physiological leukocyte rolling. Adhesive interactions between cells play a central role in the function of the immune system. Unique among the cell–cell interactions of the immune system is the rolling of leukocytes on activated endothelium. This rolling under hydrodynamic shear forces is a first step in directing leukocytes out of the blood stream into sites of inflammation and is mediated by the selectins, a family of extended, modular, and calcium- dependent lectin receptors (1, 2). To fulfill their physiological function, the selectins and their ligands exhibit a unique combination of mechanical and biochemical properties. They associate very fast and with high affinity and can tether cells over distances of up to 100 nm by their long, chainlike structure. The selectin-ligand complexes withstand high tensile forces and terminate their binding in a controlled way to maintain rolling without themselves being pulled out of the cell membrane.
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