The collagens are a family of highly characteristic fibrous proteins found in all multicellular

23 The collagens are a family of highly characteristic fibrous proteins found in all multicellular

animals. They are secreted by connective tissue cells, as well as by a variety of other cell types. As a major component of skin and bone, they are the most abundant proteins in mammals, constituting 25% of the total protein mass in these animals. The characteristic feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains, called α chains, are wound around one another in a ropelike superhelix. Collagens are extremely rich in proline and glycine, both of which are important in the formation of the triple-stranded helix. Proline, because of its ring structure, stabilizes the helical animals. They are secreted by connective tissue cells, as well as by a variety of other cell types. As a major component of skin and bone, they are the most abundant proteins in mammals, constituting 25% of the total protein mass in these animals. The characteristic feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains, called α chains, are wound around one another in a ropelike superhelix. Collagens are extremely rich in proline and glycine, both of which are important in the formation of the triple-stranded helix. Proline, because of its ring structure, stabilizes the helical

a side chain), glycine allows the three helical α chains to pack tightly together to form the final collagen superhelix (Figure 19-40).

So far, about 25 distinct collagen α chains have been identified, each encoded by a separate gene. Different combinations of these genes are expressed in different tissues. Although in principle more than 10,000 types of triple-stranded collagen molecules could be assembled from various combinations of the 25 or so α chains, only about 15 types of collagen molecules have been found. The main types of collagen found in connective tissues are types I, II, III, V, and XI - type I being the principal collagen of skin and bone and by far the most common. These are the fibrillar collagens and have the ropelike structure we have described for a typical collagen molecule. After being secreted into the extracellular space, these collagen molecules assemble into ordered polymers called collagen fibrils,which are thin (10-300 nm in diameter) structures, many hundreds of micrometers long in mature tissues and clearly visible in electron micrographs (Figure 19-41, and see Figure 19-39). The collagen fibrils often aggregate into larger, cablelike bundles, which can be seen in the light microscope as collagen fibers several micrometers in diameter. Types IX and XII are called fibril-associated collagens as they decorate the surface of collagen fibrils; they are thought to link these fibrils to one another and to other components in the extracellular matrix. Types IV and VII are network-forming collagens: type IV molecules assemble into a feltlike sheet or meshwork that constitutes a major part of mature basal laminae, while type

VII molecules form dimers that assemble into specialized structures called anchoring fibrils, which help attach the basal lamina of multilayered epithelia to the underlying connective tissue and therefore are especially abundant in the skin. The collagen types that we discuss are listed in Table 19-4.

Many proteins that contain a repeated pattern of amino acids have evolved by duplications of DNA sequences. The fibrillar collagens apparently arose in this way. Thus the genes that encode the α chains of most of these collagens are very large (up to 44 kilobases in length) and contain about 50 exons. Most of the exons are 54, or multiples of 54, nucleotides long, suggesting that these collagens arose by multiple duplications of a primordial gene containing 54 nucleotides and encoding exactly 6 Gly-X-Y repeats (see Figure 19-40).

Co lla g e n s Are S e c re t e d w it h a N o n h e lic a l Ex t e n s io n a t Ea c h

En d 23 , 24

The individual collagen polypeptide chains are synthesized on membrane-bound ribosomes and injected into the lumen of the endoplasmic reticulum (ER) as larger precursors, called pro- α chains. These precursors not only have the short amino-terminal signal peptide required to direct the nascent polypeptide to the ER, they also have additional amino acids, called propeptides, at both their amino- and carboxyl-terminal ends. In the lumen of the ER selected proline and lysine residues are hydroxylated to form hydroxyproline and hydroxylysine, respectively, and some of the hydroxylysine residues are glycosylated. Each pro- α chain then combines with two others to form a hydrogen-bonded, triple-stranded helical molecule known as procollagen. The secreted forms of fibrillar collagens (but not the other types of collagen) are converted to collagen molecules in the extracellular space by the removal of the propeptides (see Figure 19-43).

Hydroxylysineand hydroxyprolineresidues (Figure 19-42) are infrequently found in other animal proteins, although hydroxyproline is abundant in some proteins found in the plant cell wall. In collagen the hydroxyl groups of these amino acids are thought to form interchain hydrogen bonds that help stabilize the triple-stranded helix, and conditions that prevent proline hydroxylation, such as a deficiency of ascorbic acid (vitamin C), have serious consequences. In scurvy, the disease caused by a dietary deficiency of vitamin C that was common in sailors until the last century, the defective pro- α chains that are synthesized fail to form a stable triple helix and are immediately degraded within the cell. Consequently, with the gradual loss of the preexisting normal collagen in the matrix, blood vessels become extremely fragile and teeth become loose in their sockets. This implies that in these particular tissues degradation and replacement of collagen is relatively rapid. In many other adult tissues, however, the turnover of collagen (and other extracellular matrix macromolecules) is thought to be very slow: in bone, to take an extreme example, collagen molecules persist for about 10 years before they are degraded and replaced. By contrast, most cellular proteins have half-lives of hours or days.

Aft e r S e c re t io n Fib rilla r P ro c o lla g e n Mo le c u le s Are Cle a v e d t o Co lla g e n Mo le c u le s , W h ic h As s e m b le in t o Fib rils 23 , 24 ,