Unstable molecules form stable tissues

Collagens are major structural proteins in the extracellular matrix, making up about one-third of protein mass in higher animals. In addition to their sheer bulk, this protein family is of interest because of their diversity of structural and morphogenetic roles and the attribution of an increasing number of hereditary diseases to mutations in collagens (1–4). All collagens have a distinctive molecular conformation: a triple-helix composed of three supercoiled polyproline II-like helical chains (5–7). This triple-helical conformation places strict constraints on amino acid sequence, requiring Gly as every third residue and a high content of proline and hydroxyproline residues. There are more than 20 distinct genetic types of collagens, and the most abundant are types I, II, and III, found in fibrils with a characteristic 67-nm axial period (1). Type I collagen, a heterotrimer composed of two α1(I) chains and one α2(I) chain, forms the prominent fibrils in tendon, bone, and cornea, whereas type III collagen, a disulfide-linked homotrimer, is found together with type I in fibrils of blood vessels and skin. These fibril-forming collagens are synthesized in a procollagen form, with globular propeptides on each end of a central triple-helix (Fig. 1; ref. 3). Self-association and disulfide cross-linking of three C-propeptides are responsible for the initial events of chain selection and trimer formation, whereas subsequent events include nucleation and zipper-like folding of the triple-helix domain (8). After cleavage of the propeptides, the rod-like triple-helical molecules in the matrix self-associate in a staggered array, forming fibrils and interacting with other matrix molecules to provide the strength, flexibility, or compression required for each tissue. Collagen fibers are inherently stable structures, having lifetimes of at least 6 months, and often much longer. Turnover is accomplished through a specialized family of tightly regulated matrix metalloproteinases, because triple-helices are resistant …