Type I collagen is the most abundant protein in humans, and it helps to maintain the integrity of many tissues via its interactions with cell surfaces, other extracellular matrix molecules, and growth and differentiation factors. Nearly 50 molecules have been found to interact with type I collagen, and for about half of them, binding sites on this collagen have been elucidated. In addition, over 300 mutations in type I collagen associated with human connective tissue disorders have been described. However, the spatial relationships between the known ligand-binding sites and mutation positions have not been examined. To this end, here we have created a map of type I collagen that includes all of its ligand-binding sites and mutations. The map reveals the existence of several hot spots for ligand interactions on type I collagen and that most of the binding sites locate to its C-terminal half. Moreover, on the collagen fibril some potentially relevant relationships between binding sites were observed including the following: fibronectin-and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may potentially impact upon collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype. These and other observations presented here may provide novel insights into evaluating type I collagen functions and the relationships between its binding partners and mutations.

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...

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Summary The Italian Branch of EDTNA/ERCA organised a national, epidemiological, retrospective study to collect data and implement preventative measures for the spread of HCV infection in dialysis units. A questionnaire was sent to staff in 830 dialysis centres to collect information relating to 1996. Data are presented on incidence/prevalence of HCV infection, antibodies, viraemia and mortality, and comparison of the management of HCV between centres. At variance with the recommendations of the Official Health Organisations, dedicated machines and separate rooms are used in many centres and this paper concludes with recommendations for units, in particular those units with a low prevalence of antiHCV positive patients.