Abstract
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.
Highlights
We identified 11 such areas (Fig. 4A), many of which overlap with hot spots for ligand interactions (Fig. 4A, regions 2 and 6 –11)
We speculate that the sites silent for mutations in type I collagen are critical for collagen function and may act cooperatively to promote collagen fibrillogenesis or to facilitate interactions with type I collagen-associated molecules, such as type V collagen (64), proposed to be important for fibril assembly or function
It was found that for several types of connective tissue disorders mutation positions within the D-period appeared to correlate with disease phenotype
Summary
Map Construction—To examine the spatial relationships between important sites on type I collagen and to thereby identify collagenbinding ligands that might functionally impact upon each other, we have placed the type I collagen interactive sites and mutations reported in the literature onto a map of the D-period repeat of the type I collagen fibril (Fig. 2). Identifying Interrelationships between Sites—Using the fibril map, identifications of potential interacting sites on type I collagen were achieved in three ways: first, as collagen sequences to which more than one ligand has been shown to bind or which are near neighbors on the same monomer; second, as sequences that fall within the borders of a fibril region shown to bind a particular ligand; and third, as binding sites on adjacent monomers that might impact upon each other The latter must take into account the fact that monomers are proposed to be arranged in 5-mer bundles, their precise lateral arrange-. A GAG chain of 20 kDa would be about 40 nm long (17) and could potentially span up to around 25 monomers across the fibril and about 60% of the D-period width
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