Collagen Type I Is Composed Of A Triple Helix Structure Forms Fibrils

All collagen types have a triple helical structure. In some collagens, the entire molecule is triple helical, whereas in others the triple helix may involve only a fraction of the structure. Mature collagen type I, containing approximately 1000 amino acids, belongs to the former type; in it, each polypeptide subunit or alpha chain is twisted into a left-handed helix of three residues per turn (Figure 48-1). Three of these alpha chains are then wound into a right-handed superhelix, forming a rod-like molecule 1.4 nm in diameter and about 300 nm long. A striking characteristic of collagen is the occurrence of glycine residues at every third position of the triple helical portion of the alpha chain. This is necessary because glycine is the only amino acid small enough to be accommodated in the limited space available down the central core of the triple helix. This repeating structure, represented as (Gly-X-Y)n, is an absolute requirement for the formation of the triple helix. While X and Y can be any other amino acids, about 100 of the X positions are proline and about 100 of the Y positions are hydroxyproline. Proline and hydroxy-proline confer rigidity on the collagen molecule. Hy-droxyproline is formed by the posttranslational hy-droxylation of peptide-bound proline residues catalyzed by the enzyme prolyl hydroxylase, whose cofactors are ascorbic acid (vitamin C) and a-ketoglutarate. Lysines

Table 48-1. Types of collagen and their genes.

Table 48-1. Types of collagen and their genes.

Type

Genes

Tissue

I

COL1A1, COL1A2

Most connective tissues, including bone

II

COL2A1

Cartilage, vitreous humor

III

COL3A1

Extensible connective tissues such as skin, lung, and the vascular system

IV

COL4A1-COL4A6

Basement membranes

V

COL5A1-COL5A3

Minor component in tissues containing collagen I

VI

COL6A1-COL6A3

Most connective tissues

VII

COL7A1

Anchoring fibrils

VIII

COL8A1-COL8A2

Endothelium, other tissues

IX

COL9A1-COL9A3

Tissues containing collagen II

X

COL10A1

Hypertrophic cartilage

XI

COL11A1, COL11A2, COL2A1

Tissues containing collagen II

XII

COL12A1

Tissues containing collagen I

XIII

COL13A1

Many tissues

XIV

COL14A1

Tissues containing collagen I

XV

COL15A1

Many tissues

XVI

COL16A1

Many tissues

XVII

COL17A1

Skin hemidesmosomes

XVIII

COL18A1

Many tissues (eg, liver, kidney)

XIX

COL19A1

Rhabdomyosarcoma cells

1Adapted slightly from Prockop DJ, Kivirrikko KI: Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995;64:403.

2The types of collagen are designated by Roman numerals. Constituent procollagen chains, called proa chains, are numbered using Arabic numerals, followed by the collagen type in parentheses. For instance, type I procollagen is assembled from two proa1(I) and one proa2(I) chain. It is thus a heterotrimer, whereas type 2 procollagen is assembled from three proa1(II) chains and is thus a homotrimer. The collagen genes are named according to the collagen type, written in Arabic numerals for the gene symbol, followed by an A and the number of the proa chain that they encode. Thus, the COL1A1 and COL1A2 genes encode the a1 and a2 chains of type I collagen, respectively.

Table 48-2. Classification of collagens, based primarily on the structures that they form.1

Class

Type

Fibril-forming

I, II, III, V, and XI

Network-like

IV, VIII, X

FACITs2

IX, XII, XIV, XVI, XIX

Beaded filaments

VI

Anchoring fibrils

VII

Transmembrane domain

XIII, XVII

Others

XV, XVIII

1Based on Prockop DJ, Kivirrikko KI: Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995;64:403.

2FACITs = fibril-associated collagens with interrupted triple helices.

1Based on Prockop DJ, Kivirrikko KI: Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995;64:403.

2FACITs = fibril-associated collagens with interrupted triple helices.

67 nm

Fibril

67 nm

Molecule

Triple helix

Alpha chain nuo(\)o'\)onaonijOriu Amino acid sequence - G'Y - x - Y - G'Y - x - Y - G'Y - x - Y -

Alpha chain nuo(\)o'\)onaonijOriu Amino acid sequence - G'Y - x - Y - G'Y - x - Y - G'Y - x - Y -

Figure 48-1. Molecular features of collagen structure from primary sequence up to the fibril. (Slightly modified and reproduced, with permission, from Eyre DR: Collagen: Molecular diversity in the body's protein scaffold. Science 1980;207:1315. Copyright © 1980 by the American Association for the Advancement of Science.)

in the Y position may also be posttranslationally modified to hydroxylysine through the action of lysyl hydroxylase, an enzyme with similar cofactors. Some of these hydroxylysines may be further modified by the addition of galactose or galactosyl-glucose through an O-glycosidic linkage, a glycosylation site that is unique to collagen.

Collagen types that form long rod-like fibers in tissues are assembled by lateral association of these triple helical units into a "quarter staggered" alignment such that each is displaced longitudinally from its neighbor by slightly less than one-quarter of its length (Figure 48-1, upper part). This arrangement is responsible for the banded appearance of these fibers in connective tissues. Collagen fibers are further stabilized by the formation of covalent cross-links, both within and between the triple helical units. These cross-links form through the action of lysyl oxidase, a copper-dependent enzyme that oxidatively deaminates the e-amino groups of certain lysine and hydroxylysine residues, yielding reactive aldehydes. Such aldehydes can form aldol condensation products with other lysine- or hydroxylysine-derived aldehydes or form Schiff bases with the e-amino groups of unoxidized lysines or hydroxy-lysines. These reactions, after further chemical rearrangements, result in the stable covalent cross-links that are important for the tensile strength of the fibers. Histidine may also be involved in certain cross-links.

Several collagen types do not form fibrils in tissues (Table 48-2). They are characterized by interruptions of the triple helix with stretches of protein lacking Gly-X-Y repeat sequences. These non-Gly-X-Y sequences result in areas of globular structure interspersed in the triple helical structure.

Type IV collagen, the best-characterized example of a collagen with discontinuous triple helices, is an important component of basement membranes, where it forms a mesh-like network.

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