PubMed · 6532053
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M Matsuda. 1984. Abnormal fibrinogens.. https://pubmed.ncbi.nlm.nih.gov/6532053/
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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 alphaC-domains and its central region.
Specific molecular interactions mediated by the N-terminus of fibrinogen's Bbeta chain were revealed using laser tweezers-based force spectroscopy. We examined interactions between fibrinogen fragments representing the center of the molecule, NDSK, desA-NDSK, and desAB-NDSK, and two recombinant fibrinogens, gammaD364H and gammaD364A, which have nonfunctional gamma-chain polymerization sites to prevent the dominant knob-hole binding. Interactions between desA-NDSK, where the N-terminus of the Bbeta chain is present, and the fibrinogen variants showed a complex spectrum of rupture forces which disappeared with desAB-NDSK, lacking both FpA and FpB. The interactions between desA-NDSK and gammaD364H or gammaD364A were inhibited by addition of soluble FpB, but not FpA or the polymerization inhibitor peptides GPRP and GHRP. When gammaD364H fibrinogen was replaced with its X-fragment lacking alphaC- domains or with fragment D, the strongest component of the rupture force spectrum disappeared, suggesting interactions between the uncleaved FpB and the alphaC-domain. Electron microscopy confirmed the binding of desA-NDSK to either D or E regions of fibrinogen as well as to alphaC-domains. The data demonstrate the existence of weak transient interactions within and between fibrin molecules mediated by the N-terminus of the fibrinogen Bbeta chain.
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