Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates

Abstract

Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a twodimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.Type I collagen is the most abundant protein in humans and other vertebrates, comprising much of the fibrous extracellular matrix scaffold of bones, tendons, skin, and many other tissues (1-4). In general, type I collagen and its binding partners are proposed to provide mechanical strength and form to tissues. Collagenous scaffolds are laid down and remodeled by cells and are also a predominant substrate for cell interactions, migration, and differentiation. Consequently, various debilitating human diseases are associated with type I collagen mutations, including osteogenesis imperfecta (OI, 2 brittle bone disease), Ehlers Danlos syndrome, vascular disorders, and others (3, 5). Type I collagen is also employed in human medicine as hemostatic sponges and implants to repair wounds and in tissue engineering applications as scaffolds (6).Type I collagen is synthesized in the endoplasmic reticulum as ␣1 and ␣2 procollagen chains, each encoded by separate genes that are translated into proteins somewhat longer than 1000 amino acid residues (3, 7). Nucleation domains on the C-terminal propeptide promote the polymerization of two ␣1 and one ␣2 chains into the procollagen triple helical monomer (Fig. 1, A and B). The triple helical domain of procollagen is composed of contiguous glycine-X-Y tri-peptide repeats, with the obligate glyci...

Osteogenesis imperfecta

“…The three major ligand binding regions (MLBRs; FIG. 2) identified along the α1(I) chain 36 are particularly important for matrix quality. The C terminal MLBR3 is especially crucial for interactions of collagen with extracellular matrix pro teins; substitutions in this domain impair extracellular matrix organization and have predominantly lethal out comes 36,37 .…”

“…2) identified along the α1(I) chain 36 are particularly important for matrix quality. The C terminal MLBR3 is especially crucial for interactions of collagen with extracellular matrix pro teins; substitutions in this domain impair extracellular matrix organization and have predominantly lethal out comes 36,37 . Mutations in the C propeptide that impair α chain recognition are responsible for ER associated protein degradation activation, which favours the removal of unassembled chains 29 .…”

“…Mutations in the C propeptide that impair α chain recognition are responsible for ER associated protein degradation activation, which favours the removal of unassembled chains 29 . In the α2(I) chain, lethal regions that align with proteoglycan binding sites on collagen fibrils have been identified along the chain; mutations in these domains may severely affect proper matrix assembly 36,37 .…”

Bone Material Properties in Osteogenesis Imperfecta

“…1). (10) (18) High bone mass in C-propeptide cleavage site defects (61) Caffey disease with defect at p.Arg1014Cys (111) …”

COLdb, a database linking genetic data to molecular function in fibrillar collagens

“…Individual experiments performed on full-length proteins, proteolytic fragments, fibrils, or collagen-like peptides have provided insights into the stability, structure, synthesis, and function of fibrillar collagens, but a combined analysis of these diverse data types has been hampered by the lack of an integrated, electronic source of the data. Although some information is available online, notably the list of mutations in collagen types I and III [Dalgleish, 1997[Dalgleish, , 1998], and a printed map of the ligand-binding sites and mutations of type I collagen has been published [Di Lullo et al, 2002;Sweeney et al, 2008], much of the data on the major fibrillar collagens remains scattered in the literature. To facilitate a comprehensive analysis, we have aggregated collagen data from the literature in an electronic database named COLdb.…”