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Forced Unfolding of Coiled-Coils in Fibrinogen by Single-Molecule AFM

André E. X. Brown ^* , Rustem I. Litvinov , Dennis E. Discher   and John W. Weisel 

^* Department of Physics and Astronomy, Nano/Bio Interface Center, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, and Graduate Groups in Physics and Cell Biology & Physiology, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: Address reprint requests and inquiries to John Weisel, Tel.: 215-898-3573; E-mail: weisel{at}mail.med.upenn.edu; or Dennis Discher, Tel.: 215-898-4809; E-mail: discher{at}seas.upenn.edu.

Fibrinogen is a blood plasma protein that, after activation by thrombin, assembles into fibrin fibers that form the elastic network of blood clots. We used atomic force microscopy to study the forced unfolding of engineered linear oligomers of fibrinogen, and we show that forced extension of the oligomers produces sawtooth patterns with a peak-to-peak length consistent with the independent unfolding of the coiled-coils in a cooperative two-state manner. In contrast with force plateaus seen for myosin coiled-coils that suggested rapid refolding of myosin, Monte Carlo simulations of fibrinogen unfolding confirm that fibrinogen refolding is negligible on experimental timescales. The distinct behavior of fibrinogen seems to be due to its topologically complex coiled-coils and an interaction between fibrinogen's C-domains and its central region.

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