Osteogenesis Imperfecta Murine: Interaction Between Type I Collagen Homotrimers

Types I, II, and III collagens are believed to have evolved from the same homotrimer ancestor and they have substantial sequence homology, but type I molecules are α1(I)2α2(I) heterotrimers, unlike homotrimeric types II and III. It is believed that the α2(I) chain first appeared in lower vertebrates and that it plays a particularly important role in bone formation. For instance, spontaneous mutations resulting in non- functional α2 chains and formation of type I homotrimers cause severe bone pathology (osteogenesis imperfecta) in humans and in animals. However, the exact role of the α2 chain is not known. Here, we report measurements of intermolecular forces between collagen helices in native and reconstituted fibers composed of type I homotrimers, heterotrimers and their mix. For comparison, we report forces between type II homotrimers in reconstituted fibers. In agreement with previous studies, we find that the absence of the α2 chain reduces temperature-favored attraction between collagen helices, either because of the difference in amino acid sequence of the α1 and α2 chains or because of more extensive post-translational modification of homotrimers. We find that forces between helices in fibers from type I (as well as type II) homotrimers are not sensitive to pH between pH 6 and 7.5, in contrast to type I heterotrimers. Apparently, the effect of pH is related to extra histidine residues present on α2 chains but not on α1 chains. Finally, our measurements indicate that the α2 chain is responsible for binding some soluble compound(s), possibly glycosaminoglycans, whose displacement results, e.g., in the loss of tendon crystallinity. The ability of the α2 chain to bind non-collagen matrix components may be particularly important for bone matrix formation and mineralization.