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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2944-2951.
Prepublished online as a Blood First Edition Paper on July 5, 2005; DOI 10.1182/blood-2005-05-2039.
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Submitted May 20, 2005
Accepted June 22, 2005
Polymerization of fibrin: specificity, strength, and stability of knob:hole interactions studied at the single molecule level
Rustem I Litvinov*, Oleg V Gorkun, Scott F Owen, Henry Shuman, and John W Weisel
Department of Cell & Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* Corresponding author; email: litvinov{at}mail.med.upenn.edu.
Using laser tweezers, we measured for the first time the forces of individual knob-into-hole interactions underlying fibrin polymerization. Exposure of A-knobs in desA-fibrin or its fragment from the central part of the molecule (N-terminal disulphide knot, NDSK) resulted in strong interactions with fibrinogen or fragment D (containing only a- and b-holes), producing a binding strength of ~125-130 pN. The interactions were not present in the absence of either knobs or holes and were abrogated by a specific inhibitor of fibrin polymerization, a peptide mimic of the A-knob (GPRPam). Exposure of both the A- and B-knobs in desAB-fibrin or desAB-NDSK did not change the rupture force spectra compared to the desA-molecules, and their interactions with fibrinogen remained highly sensitive to GPRPam but not to GHRPam (B-knob), suggesting that neither A:b nor B:b nor B:a contacts contributed significantly to binding strength in addition to A:a contacts. The A:a interactions had a relatively small zero-force off-rate of ~10-4 s-1 and tight knob-to-hole contacts characterized by a transition state distance of ~0.3 nm. The results demonstrate that the knob-hole binding during thrombin-induced fibrin polymerization is driven by strong, stable, and highly specific A:a bonding, while A:b, B:b, or B:a interactions were not detected.
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