![]() First, the crystallographic data available are incomplete. Yet using the crystal structures of fibrinogen or fibrin is challenging. Therefore, fibrin oligomers and protofibrils can be reconstructed using resolved crystal structures of the human fibrinogen molecule and parts of fibrinogen and fibrin molecules, including the fibrinogen fragment D and the double-D fragment from crosslinked fibrin (see Table S1). The monomeric fibrin is essentially identical in structure and composition to fibrinogen except for small fibrinopeptides A and B, which are cleaved when fibrinogen is converted to fibrin, and αC domains, which are bound to the central nodule in fibrinogen but detached in fibrin ( Medved et al., 2001). ![]() These branches form a three-dimensional fibrin network called a clot ( Weisel and Litvinov, 2017). Fibrin protofibrils self-associate laterally to form twisted fibers of variable thickness. This growth continues until the fibrin oligomers reach the critical length of protofibrils: oligomers made of ~20–25 fibrin monomers. Furthermore, fibrin monomers add longitudinally via the inter-strand A-a knob-hole bond formation and intra-strand D-D interactions to form fibrin oligomers. The D:D interface provides a junction between the monomers in one of the two strands in a fibrin trimer. ![]() The addition of a third molecule is accompanied by an end-to-end association where, in addition to the A-a knob-hole interactions, the globular D regions of two adjacent molecules form the D:D interface. Exposure of knobs ‘‘A’’ is necessary and sufficient to form fibrin through the interaction with holes ‘‘a.’’ The release of fibrinopeptides B exposes an N-terminal β-chain motif GHRP, called knob ‘‘B’’, which is complementary to hole ‘‘b’’ located in the b nodule of another fibrin molecule.įibrin polymerization begins when two monomeric fibrin molecules interact in a half-staggered fashion through the A-a knob-hole interaction. The release of fibrinopeptides A exposes an N-terminal α-chain motif GPR, called knob ‘‘A’’, which binds to constitutively exposed hole ‘‘a’’ in the γ nodule of another fibrin molecule ( Everse et al., 1998 Kostelansky et al., 2002), resulting in the formation of an A-a knob-hole non-covalent bond ( Litvinov et al., 2005). Because of the fundamental biological and medical importance, molecular mechanisms of fibrin formation as well as fibrin structure and properties continue to be major areas of research ( Weisel and Litvinov, 2013, 2017 Litvinov and Weisel, 2016).įibrin formation is initiated by the cleavage of fibrinopeptides A and B from the N termini of Aα and Bβ chains of fibrinogen, respectively, to produce fibrin monomer. Fibrin is widely used as a versatile biomaterial in a variety of applications, such as hemostatic sealants, tissue engineering, as a delivery vehicle for cells, drugs, growth factors, and genes, and matrices for cell culturing ( Janmey et al., 2009 Radosevich et al., 1997). Fibrin is also a major component of the extracellular matrix and is involved in a broad range of cellular processes, including cell adhesion, migration, proliferation and differentiation, wound healing, angiogenesis, and inflammation ( Weisel and Litvinov, 2017 Litvinov and Weisel, 2017). Atomic structures of protofibrils provide a basis to understand mechanisms of early stages of fibrin polymerization.įibrin is an end product of blood clotting that forms the scaffold of hemostatic clots and obstructive thrombi in blood vessels. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic parameters of fibrin oligomers. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with γ- γ crosslinking, A:a and B:b knob-hole bonds, and αC regions-all important structural determinants not resolved crystallographically. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. The space-filling fibrin network is a major part of clots and thrombi formed in blood.
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