Mechanism of Fibrin(ogen) Forced Unfolding

Zhmurov, Artem; Brown, André E. X.; Litvinov, Rustem I.; Dima, Ruxandra I.; Weisel, John W.; Barsegov, Valeri

doi:10.1016/j.str.2011.08.013

Cited by 119 publications

(158 citation statements)

References 52 publications

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“…The resulting computational predictions have been confirmed by our joint studies combining simulation and atomic force microscopy experiments (28). Importantly, this model, which enables one to follow the dynamics of proteins on experimental timescales up to seconds (29), has been successfully applied to study the mechanical response of systems from kinesin (30) to fibrinogen (31) to viral capsids (32) to full microtubules (33) as well as to provide insights into protein refolding following chemical denaturation (34,35).…”

Section: Molecular Simulations By Forced Unfolding Of the Nbd Providementioning

confidence: 54%

Nucleotides regulate the mechanical hierarchy between subdomains of the nucleotide binding domain of the Hsp70 chaperone DnaK

Bauer

Merz

Pelz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The regulation of protein function through ligand-induced conformational changes is crucial for many signal transduction processes. The binding of a ligand alters the delicate energy balance within the protein structure, eventually leading to such conformational changes. In this study, we elucidate the energetic and mechanical changes within the subdomains of the nucleotide binding domain (NBD) of the heat shock protein of 70 kDa (Hsp70) chaperone DnaK upon nucleotide binding. In an integrated approach using single molecule optical tweezer experiments, loop insertions, and steered coarse-grained molecular simulations, we find that the C-terminal helix of the NBD is the major determinant of mechanical stability, acting as a glue between the two lobes. After helix unraveling, the relative stability of the two separated lobes is regulated by ATP/ADP binding. We find that the nucleotide stays strongly bound to lobe II, thus reversing the mechanical hierarchy between the two lobes. Our results offer general insights into the nucleotide-induced signal transduction within members of the actin/sugar kinase superfamily.ATPase | laser trapping | elasticity | force | protein extension

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Section: Molecular Simulations By Forced Unfolding Of the Nbd Providementioning

confidence: 54%

Nucleotides regulate the mechanical hierarchy between subdomains of the nucleotide binding domain of the Hsp70 chaperone DnaK

Bauer

Merz

Pelz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The D-D interactions are weak and yield first upon forced stretching of fibrin (ogen) oligomers. 18 Studies on natural and recombinant fibrinogen variants revealed that the residues g275, g308, and g309 are essential for D:D interactions and the elongation of fibrin strands. [19][20][21] Additional fibrin monomers can add longitudinally to the dimer and trimer to form larger oligomers, which lengthen further to make protofibrils, a critically important intermediate product of fibrin polymerization, which is capable of lateral aggregation, leading to the formation of fibers (Figure 2).…”

Section: 10mentioning

confidence: 99%

Mechanisms of fibrin polymerization and clinical implications

Weisel

Litvinov

2013

Blood

411

363

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Research on all stages of fibrin polymerization, using a variety of approaches including naturally occurring and recombinant variants of fibrinogen, x-ray crystallography, electron and light microscopy, and other biophysical approaches, has revealed aspects of the molecular mechanisms involved. The ordered sequence of fibrinopeptide release is essential for the knob-hole interactions that initiate oligomer formation and the subsequent formation of 2-stranded protofibrils. Calcium ions bound both strongly and weakly to fibrin(ogen) have been localized, and some aspects of their roles are beginning to be discovered. Much less is known about the mechanisms of the lateral aggregation of protofibrils and the subsequent branching to yield a 3-dimensional network, although the aC region and B:b knob-hole binding seem to enhance lateral aggregation. Much information now exists about variations in clot structure and properties because of genetic and acquired molecular variants, environmental factors, effects of various intravascular and extravascular cells, hydrodynamic flow, and some functional consequences. The mechanical and chemical stability of clots and thrombi are affected by both the structure of the fibrin network and cross-linking by plasma transglutaminase. There are important clinical consequences to all of these new findings that are relevant for the pathogenesis of diseases, prophylaxis, diagnosis, and treatment. (Blood. 2013;121(10):1712-1719 IntroductionFibrin polymer is an end product of the enzymatic cascade of blood clotting. In vivo formation of the polymeric fibrin network, along with platelet adhesion and aggregation, are the key events in salutary stopping of bleeding at the site of injury (hemostasis) as well as in pathological vascular occlusion (thrombosis). Fibrin polymerization comprises a number of consecutive reactions, each affecting the ultimate structure and properties of the fibrin scaffold. These properties determine the development and outcomes of various diseases, such as heart attack, ischemic stroke, cancers, trauma, surgical and obstetrical complications, hereditary and acquired coagulopathies, and thrombocytopathies. In addition to providing a better understanding of the pathogenesis of such disorders, the knowledge of the molecular mechanisms of fibrin formation provides a foundation for new diagnostic tools and therapeutic approaches. Fibrinopeptide releaseFibrinogen is 45 nm-long and made up of 6 paired polypeptide chains (Aa Bb g) 2 held together by 29 disulfide bonds. There are now crystal structures of large parts of fibrinogen, including the g-and b-nodules, the coiled coil, and the central nodule.1 Still missing in the crystal structures are the flexible NH 2 -terminal (N-terminal) ends of the Aa-chains and the carboxyl-terminal (C-terminal) portion of the Aa-chain, but modern simulation techniques make possible partial computational reconstructions of these parts of fibrin(ogen) (Figure 1).Fibrin polymerization is initiated by the thrombin cleavage of fibrinopeptides A (...

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“…In fact, the stiffness of fibrin gels can be increased up to 20 fold under application of tensile forces [39]. It was also recently found that the stepwise unfolding of fibrin(ogen) molecules at the γC nodule and the reversible extension-contraction at the αC coiled-coil region further contribute to the extensibility and strain stiffening properties of fibrin gels [42][43][44][45]. The unfolding of these regions exposes hydrophobic domains that cause a further loss of water in fibrin clots.…”

Section: The Clot Backbone: Fibrinogen and Fibrin Networkmentioning

confidence: 99%