Abstract
Type I collagen, the predominant protein of vertebrates, assembles into fibrils that orchestrate the form and function of bone, tendon, skin, and other tissues. Collagen plays roles in hemostasis, wound healing, angiogenesis, and biomineralization, and its dysfunction contributes to fibrosis, atherosclerosis, cancer metastasis, and brittle bone disease. To elucidate the type I collagen structure-function relationship, we constructed a type I collagen fibril interactome, including its functional sites and disease-associated mutations. When projected onto an X-ray diffraction model of the native collagen microfibril, data revealed a matrix interaction domain that assumes structural roles including collagen assembly, crosslinking, proteoglycan (PG) binding, and mineralization, and the cell interaction domain supporting dynamic aspects of collagen biology such as hemostasis, tissue remodeling, and cell adhesion. Our type III collagen interactome corroborates this model. We propose that in quiescent tissues, the fibril projects a structural face; however, tissue injury releases blood into the collagenous stroma, triggering exposure of the fibrils’ cell and ligand binding sites crucial for tissue remodeling and regeneration. Applications of our research include discovery of anti-fibrotic antibodies and elucidating their interactions with collagen, and using insights from our angiogenesis studies and collagen structure-function model to inform the design of super-angiogenic collagens and collagen mimetics.
Highlights
Collagens are among the most ubiquitous and complex of the vertebrate extracellular matrix (ECM) macromolecules [1,2,3,4,5]
For binding of ligands to the collagen fibrils, we identified some unobstructed sites, including glycoprotein VI (GPVI) [51], Endo180 [52,53], osteoclast-associated receptor (OSCAR; not shown on collagen interactome) [54], P986
The model we propose for the anti-α2(I) chain—its C-terminal telopeptide (α2Ct) antibody-collagen fibril interaction would provide a blue print for other interactions with anti-fibrotic potential
Summary
Collagens are among the most ubiquitous and complex of the vertebrate extracellular matrix (ECM) macromolecules [1,2,3,4,5]. The extent of the triple helical region, along with the presence of non-triple helical regions, determines the type of aggregate collagen molecules make, and how they contribute to the intricate ECM scaffold that makes up the internal architecture of the vertebrate body. Type I collagen is the prototypical collagen that aggregates into fibrils It is the most abundant protein in the human body, comprising about 7 kg of the dry weight of the human adult. Type I collagen comprises much of the substance of connective tissues including tendon, ligaments and skin, and most of the organic phase of bone, and supports and provides form to many other tissues of the vertebrate body via the connective tissue proper [1,3,8]. We will discuss how our findings inform applications including the design and discovery of anti-fibrotic and pro-angiogenic therapies
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