Chapter 2. Review of the literature

The word “collagen” originates from the mid 19^th century and it means a constituent of the connective tissue that produces glue when boiled. Although the early histologists knew about the presence of fibers in connective tissues in the 19^th century, it was not until the 1950s that the building unit of the collagen fiber, a collagen molecule, was identified (for review, see van der Rest & Garrone, 1991). Thereafter, it was realized that a similar collagenous sequence was shared by a number of ECM proteins, and the existence of a protein family became evident. This chapter provides a brief overview of vertebrate collagen types, their genes and tissue locations, with special emphasis on the latest developments of the family of type XV and XVIII collagens. The role of collagens in the development and etiology of various diseases will be discussed, as well as the contribution of the use of transgenic technology in collagen research. A short discussion of basement membranes (BM) is included in view of its relevance to the results obtained in this research.

For a protein to be classified as collagen it should have at least one domain in the characteristic triple helical conformation and it should form supramolecular aggregates in the ECM. All collagens contain two distinct types of domains, the triple helical, collagenous (COL) domains and the globular, noncollagenous (NC) domains. The size, number and the distribution of the two domain types vary between individual collagen types. The characteristic triple-helical conformation is achieved as three identical (homotrimer) or dissimilar (heterotrimer) polypeptide chains, called α-chains, with repeated Gly-X-Y sequences wind around each other. The presence of glycine as every third amino acid is essential, since a larger amino acid would not fit into the center of the helix. The X and Y positions are frequently occupied by proline and hydroxyproline, respectively. In addition, some lysine residues are modified by hydroxylation and glycosylation. Collagen biosynthesis is a complex process involving a number of unique post-translational modifications and eight specific post-translational enzymes. (For reviews, see Burgeson & Nimni, 1992; Hulmes, 1992; Kivirikko, 1993; Prockop & Kivirikko, 1995; Myllyharju & Kivirikko, 2001)

The collagen family is composed of 23 collagen types and 38 genetically distinct α-chains, four of which are currently under characterization (for reviews, see Vuorio & de Crombrugghe, 1990; van der Rest & Garrone, 1991; Burgeson & Nimni, 1992; Hulmes, 1992; Kielty et al., 1993; Kivirikko, 1993; Mayne & Brewton, 1993; van der Rest & Bruckner, 1993; Pihlajaniemi & Rehn, 1995; Prockop & Kivirikko, 1995; Myllyharju & Kivirikko, 2001). The various collagen types, their constituent chains, chain compositions, and occurrence in tissues are summarized in Table 1. A brief discussion is provided below to provide a necessary basis for further discussions on the gene structures and the role of collagens in development and various human diseases. Collagens can be divided into two major groups based on similarities in the supramolecular assemblies, primary structures, and other characteristics - the fibril-forming collagens and the non-fibril forming collagens. The latter group can be further divided into several subgroups.

Left outside the collagen superfamily are 15 proteins that contain triple-helical collagenous domains, but lack one or more of the criteria for classification as collagens (for example, are not structural components of ECMs) (for reviews, see Myllyharju & Kivirikko, 2001).