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Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond
Evan Evans1, Andrew Leung, Volkmar Heinrich
1Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. evanse@bu.edu
Summary
Biomolecular bonds, like leukocyte adhesion bonds, can have dual failure pathways. A novel "jump/ramp" force method reveals force history controls these pathways, acting as a mechanochemical switch.
Area of Science:
- Biophysics
- Molecular Mechanics
- Cell Adhesion
Background:
- Biomolecular bond strength often correlates with the rate of force application, suggesting single-pathway dissociation.
- Leukocyte adhesion molecules, such as P-selectin glycoprotein ligand 1 (PSGL-1) and P-selectin, are crucial for immune cell trafficking.
Purpose of the Study:
- To investigate the mechanical properties and failure kinetics of the PSGL-1-P-selectin bond under varying force loading rates.
- To explore the existence of multiple dissociation pathways and the role of force history in bond rupture.
Main Methods:
- Utilized a sensitive force probe to measure the mechanical strength and lifetime of PSGL-1-P-selectin bonds.
- Applied a novel 'jump/ramp' force spectroscopy technique to probe bond behavior under different loading conditions.
- Analyzed failure kinetics by varying the rate of force application and employing force jumps.
Main Results:
- Observed a single-pathway failure mechanism for PSGL-1-P-selectin bonds loaded at rates between 300 and 30,000 pN/sec.
- Discovered anomalous bond weakening and faster dissociation below 300 pN/sec, indicating a potential second failure pathway.
- Demonstrated that a preliminary force 'jump' followed by a slow ramp (jump/ramp) stabilized the bond and revealed single-pathway kinetics across all tested rates.
- Identified that force history dictates which of two distinct dissociation pathways is engaged, functioning as a mechanochemical switch.
Conclusions:
- The PSGL-1-P-selectin bond exhibits mechanochemical switch-like behavior, with force history determining its mechanical response and failure pathway.
- Structural variations in PSGL-1 and sialyl LewisX significantly alter bond failure kinetics, suggesting a structural basis for the dual pathways.
- This dual-pathway mechanism may explain the 'catch bond' phenomenon observed under constant force conditions, where bond strength increases with force.