TYPE I COLLAGEN HOMOTRIMERS; THEIR ROLE IN COLLAGEN FIBRIL FORMATION AND TISSUE REMODELING
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Formation and remodeling of type I collagen fibril networks are paradigms of biopolymer self-assembly, yet many of their aspects remain poorly understood. Type I collagen is the most abundant vertebrate protein which self assembles into fibrils and hierarchical fibril network structures, forming scaffolds of bone, skin, tendons and other tissues. The normal isoform of type I collagen is a heterotrimer of two &alpha1(I) and one &alpha2(I) chains, but homotrimers of three &alpha1(I) chains have been reported, e.g., in cancer and fibrosis. Despite their importance in various disorders, very little is known about potential effects of the type I collagen homotrimers on self-assembly, physical properties, and remodeling of collagen fibrils and fibril networks. Thus, we selected characterization of these effects and understanding the underlying physical mechanisms as the topic of the present thesis. Some of our most important findings were: (i) different nucleation mechanism and morphology in homotrimer fibrils compared to the normal heterotrimers fibrils; (ii) segregation of the homo- and heterotrimers within fibrils; (iii) increased bending rigidity of homotrimer fibrils; and (iv) homotrimer resistance to cleavage by enzymes responsible for fibril degradation and remodeling due to increased triple helix stability at the cleavage site. The corresponding in vitro experiments and theoretical analysis of the results suggested drastically different physics of the fibril networks composed of the homo/heterotrimer mixtures and pointed to a potential role of these physics in various disorders, e.g., in cancer and fibrosis pathology.