Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing

Abstract

Significance: Fibrinogen-related proteins (FRePs) comprise an intriguing collection of extracellular molecules, each containing a conserved fibrinogen-like globe (FBG). This group includes the eponymous fibrinogen as well as the tenascin, angiopoietin, and ficolin families. Many of these proteins are upregulated during tissue repair and exhibit diverse roles during wound healing. Recent Advances: An increasing body of evidence highlights the specific expression of a number of FRePs following tissue injury and infection. Upon induction, each FReP uses its FBG domain to mediate quite distinct effects that contribute to different stages of tissue repair, such as driving coagulation, pathogen detection, inflammation, angiogenesis, and tissue remodeling. Critical Issues: Despite a high degree of homology among FRePs, each contains unique sequences that enable their diversification of function. Comparative analysis of the structure and function of FRePs and precise mapping of regions that interact with a variety of ligands has started to reveal the underlying molecular mechanisms by which these proteins play very different roles using their common domain. Future Directions: Fibrinogen has long been used in the clinic as a synthetic matrix serving as a scaffold or a delivery system to aid tissue repair. Novel therapeutic strategies are now emerging that harness the use of other FRePs to improve wound healing outcomes. As we learn more about the underlying mechanisms by which each FReP contributes to the repair response, specific blockade, or indeed potentiation, of their function offers real potential to enable regulation of distinct processes during pathological wound healing.

Kim S. Midwood, PhD

Figure 1.

Fibrinogen and its C-terminal globular domain. (A) Schematic structure of fibrinogen showing the central nodule, coiled-coil domain, and α, β, and γ C-terminus domains. (B) Three-dimensional structure of the γ C-terminus globule showing its constituent three subdomains: A, B, and P. The A subdomain is at the N-terminus of the globule and consists of ∼50 amino acids. The B subdomain is in the middle of the structure and comprises ∼100 residues. Finally, at the C-terminus is the P subdomain, which contains ∼100 amino acids. This image was modified from the Yee et al. protein data bank number 1FID and colored using the PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Domain organization of human FRePs. (A) Angiopoietins 1, 2, and 4 are found in humans; angiopoietin 3 exists only in mice. Angiopoietins contain an N-terminal superclustering domain, followed by a coiled-coil domain, in which the number of amino acids varies between family members, and the C-terminus is capped by the FBG domain. (B) Angiopoietin-related proteins are structurally similar to angiopoietins. Seven have been reported in humans. They lack a superclustering domain, instead containing a proline-rich region before the FBG domain. (C) Fibroleukin contains a coiled-coil domain and a C-terminal FBG domain. (D) FIBCD-1 is the only FReP that is not secreted; it contains a transmembrane domain, followed by coiled-coil domain and FBG domain. (E) Three ficolins are found in humans: L-, M-, and H-ficolin. They contain an N-terminal collagen-like domain, which includes a cysteine-rich region and a neck region that connects with the FBG domain. These proteins have a unique mode of oligomerization; three coil-coiled chains interlace forming a collagen-like helix that brings three FBG domains together to create a trimer at the C-terminus, and (F) Tenascins are a family of four extracellular matrix glycoproteins, tenascin-C, -R, -W, and -X. Tenascins have an N-terminal region that contains a coiled-coil structure and disulfide bonds necessary for oligomer formation. Next are the EGF-like repeats, followed by FNIII, whose number varies among the tenascins, and then the FBG domain. EGF, epidermal growth factor; FBG, fibrinogen-like globe; FIBCD-1, fibrinogen C domain-containing protein-1; FNIII, fibronectin type III-like domain; FRePs, fibrinogen-related proteins.

Figure 3.

Degree of identity among human FRePs. In white is the % of identity among FReP family members, and in black is the average of identity of this family with the fibrinogen γ chain. The % of identity was calculated using ClustalW pairwise alignment. There is 40% identity between the C-terminus globular domains of fibrinogen γ and β chains. Ang, angiopoietins; AngioRP, angiopoietin-related proteins; TN, tenascin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

Functions of FREPs during wound healing. Schematic representation of the roles of FRePs in the stages of wound healing. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound