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Lodish H, Berk A, Zipurskies SL, et al. Molecular Cell Biology. fourth edition. New York: W. H. Freeman; 2000.

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Collagen is the significant insoluble fibrous protein in the extracellular matrix and inconnective tworry. In reality, it is the single most plentiful protein in the animalkingdom. Tbelow are at least 16 kinds of collagen, but80 – 90 percent of the collagen in the body consistsof types I, II, and also III (Table 22-3).These collagen molecules pack together to develop lengthy thin fibrils ofsimilar structure (see Figure 5-20). TypeIV, in comparison, forms a two-dimensional reticulum; several various other kinds associatewith fibril-form collagens, linking them to each various other or to various other matrixcomponents. At one time it was assumed that all collagens were secreted byfibroblasts in connective tissue, however we currently recognize that many epithelial cellsmake certain kinds of collagens. The various collagens and also the structures they formall serve the same objective, to assist tproblems withstand extending.


The Basic Structural Unit of Collagen Is a Triple Helix

Because its abundance in tendon-affluent tworry such as rat tail renders the fibrouskind I collagen simple to isolate, it was the first to be defined. Itsstandard structural unit is a lengthy (300-nm), thin (1.5-nm-diameter) proteinthat consists of three coiled subunits: two α1(I) chains and also oneα2(I).* Each chain contains exactly 1050 amino acids wound roughly one another ina characteristic right-handed triple helix (Figure 22-11a). All collagens were eventually shown to containthree-stranded helical segments of equivalent structure; the distinct properties ofeach form of collagen are due largely to segments that interrupt the triple helixand that fold right into other kinds of three-dimensional structures.

Figure 22-11

The structure of collagen. (a) The standard structural unit is a triple-stranded helical molecule.Each triple-stranded collagen molecule is 300 nm lengthy. (b) Infibrous collagen, collagen molecules load together side by side.Adjacent molecules are disinserted (more...)

The triple-helical structure of collagen arises from an unexplained abundance ofthree amino acids: glycine, proline, and hydroxyproline. These amino acids makeup the characteristic repeating motif Gly-Pro-X, wright here X deserve to be any kind of amino acid.Each amino acid has actually a specific feature. The side chain of glycine, an H atom, isthe only one that can fit into the crowded center of a three-stranded helix.Hydrogen bonds linking the peptide bond NH of a glycine residue through a peptidecarbonyl (C═O) group in an nearby polypeptide help host the threechains together. The resolved angle of the C – Npeptidyl-proline or peptidyl-hydroxyproline bond enables each polypeptide chainto fold into a helix with a geometry such that 3 polypeptide chains cantwist together to form a three-stranded helix. Interestingly, although the rigidpeptidyl- proline linkages disrupt the packing of amino acids in an αhelix, they stabilize the rigid three-stranded collagen helix.

Collagen Fibrils Form by Lateral Interactions of Triple Helices

Many type of three-stranded form I collagen molecules load together side-by-side, formingfibrils via a diameter of 50 – 200 nm. Infibrils, surrounding collagen molecules are disinserted from one another by 67 nm,about one-quarter of their size (Figure22-11b). This staggered selection produces a striated effect that have the right to bewatched in electron micrographs of stained collagen fibrils; the characteristicpattern of bands is repeated about every 67 nm (Figure 22-11c). The distinct properties of the fibrouscollagens — forms I, II, III, andV — are because of the capability of the rodchoose triplehelices to develop such side-by-side interactions.

Short segments at either end of the collagen chains are of specific importancein the development of collagen fibrils (view Figure 22-11). These segments carry out not assume the triple-helicalconformation and contain the unexplained amino acid hydroxylysine(check out Figure 3-16). Covalent aldolcross-links form between 2 lysine or hydroxylysine residues at the C-terminusof one collagen molecule via two comparable residues at the N-terminus of anadjacent molecule (Figure 22-12). Thesecross-links stabilize the side-by-side packing of collagen molecules andgeneprice a solid fibril.


Figure 22-12

The side-by-side interactions of collagen helices are stabilizedby an aldol cross-link between 2 lysine (or hydroxylysine) sidechains. The extracellular enzyme lysyl oxidase catalyzes formation of thealdehyde groups.

Type I collagen fibrils have actually enormous tensile strength; that is, such collagencan be stretched without being broken. These fibrils, about 50 nm in diameterand also numerous micrometers long, are packed side-by-side in parallel bundles,called collagen fibers, in tendons, where they connect musclesvia bones and also have to withstand massive forces (Figure 22-13). Gram for gram, kind I collagen is stronger thansteel.

Figure 22-13

Electron micrograph of the dense connective tconcern of a chicktendon. Many of the tissue is populated by parallel type I collagen fibrils,around 50 nm in diameter, checked out right here in cross section. The cellularcontent of the tconcern is extremely low.

Assembly of Collagen Fibers Begins in the ER and Is Completed exterior theCell

Collagen biosynthesis and also assembly adheres to the normal pathmeans for a secretedprotein (watch Figure 17-13). The collagenchains are synthesized as much longer precursors calledprocollagens; the growing peptide chains areco-translationally transported right into the lumales of the stormy endoplasmic reticulum(ER). In the ER, the procollagen chain undergoes a collection of processingreactions (Figure 22-14). First, as withvarious other secreted proteins, glycosylation of procollagen occurs in the unstable ER andGolgi complicated. Galactose and glucose residues are included to hydroxylysineresidues, and lengthy oligosaccharides are added to particular asparagine residues inthe C-terminal propeptide, a segment at the C-terminus of aprocollagen molecule that is lacking from mature collagen. (The N-terminal endadditionally has a propeptide.) In enhancement, particular proline and also lysine residues in themiddle of the chains are hydroxylated by membrane-bound hydroxylases. Lastly,intrachain disulfide bonds in between the N- and also C-terminal propeptide sequencesalign the three chains before the triple helix creates in the ER. The centralparts of the chains zipper from C- to N-terminus to form the triplehelix.

Figure 22-14

Major events in the biosynthesis of fibrous collagens. Modifications of the procollagen polypeptide in the endoplasmic reticulum incorporate hydroxylation, glycosylation, and disulfide-bonddevelopment. Interchain disulfide bonds in between the C-terminalpropeptides (more...)

After handling and assembly of form I procollagen is completed, it is secretedinto the extracellular room. Throughout or adhering to exocytosis, extracellularenzymes, the procollagen peptidases, rerelocate the N-terminal and C-terminalpropeptides. The resulting protein, often called tropocollagen(or simply collagen), consists almost totally of atriple-stranded helix. Excision of both propeptides allows the collagenmolecules to polymerize right into normal fibrils in the extracellular room (seeFigure 22-14). The potentiallycatastrophic assembly of fibrils within the cell does not take place both because thepropeptides inhilittle fibril development and also because lysyl oxidase, which catalyzesdevelopment of reenergetic aldehydes, is an extracellular enzyme (check out Figure 22-12). As listed above, thesealdehydes spontaneously develop specific covalent cross-web links between twotriple-helical molecules, which stabilizes the staggered selection characteristic ofcollagen molecules and also contributes to fibril toughness.

Post-translational modification ofprocollagen is essential for the formation of mature collagen molecules and also theirassembly right into fibrils. Defects in this procedure have actually major results, asprehistoric mariners commonly knowledgeable. For instance, the activity of bothprolyl hydroxylases needs an important coelement, ascorbic acid (vitamin C).In cells deprived of ascorbate, as in the condition scurvy, theprocollagen chains are not hydroxylated sufficiently to develop stable triplehelices at normal body temperature (Figure22-15), nor can they form normal fibrils. Consequently,nonhydroxylated procollagen chains are degraded within the cell. Without thestructural assistance of collagen, blood vessels, tendons, and skin become fragile.A supply of fresh fruit offers enough vitamin C to process procollagenappropriately.

Figure 22-15

Denaturation of collagen containing a normal content ofhydroxyproline and of abnormal collagen containing nohydroxyproline. Without hydrogen bonds between hydroxyproline residues, the collagenhelix is unsteady and loses many of its helical content (more...)

Mutations in Collagen Reveal Aspects of Its Structure andBiosynthesis

Type I collagen fibrils are used as thereinforcing rods in building and construction of bone. Certain mutations in theα1(I) or α2(I) genes lead toosteogenesis imperfecta, or brittle-bone illness. The mostmajor form is an autosomal dominant, lethal condition leading to death in uteroor soon after birth. Milder forms generate a significant crippling disease. Ascan be meant, many type of cases of osteogenesis imperfecta are due to deletions oloss or part of the exceptionally long α1(I) gene. However before, a singleamino acid readjust is adequate to reason specific develops of this condition. As wehave actually seen, a glycine must be at every 3rd position for the collagen triplehelix to form; mutations of glycine to virtually any other amino acid aredeleterious, creating poorly developed and also unsecure helices. Since the triplehelix forms from the C- to the N-terminus, mutations of glycine close to theC-terminus of the α1(I) chain are commonly more deleteriousthan those near the N-terminus; the latter permit considerable areas of triplehelix to create. Mutant unfolded collagen chains carry out not leave the stormy ER offibroblasts (the cells that make a lot of of type I collagen), or they leave itslowly. As the ER becomes dilated and also broadened, the secretion of various other proteins(e.g., type III collagen) by these cells likewise is slowed down.

Due to the fact that each type I collagen molecule consists of two α1(I) andone α2(I) chains, mutations in theα2(I) chains are a lot much less damaging. To understand also thisallude, consider that in a heterozygote expushing one wild-type and one mutantα2(I) protein, 50 percent of the collagen moleculeswill certainly have actually the abnormal α2(I) chain. In comparison, if themutation is in the α1(I) chain, 75 percent of the collagenmolecules will have one or two mutant α1(I) chains. Inreality, even low expression of a mutant α1(I) gene have the right to bedeleterious, bereason the mutant chains deserve to disrupt the function of wild-typeα1(I) chains as soon as merged through them. To study suchmutations, experimenters built a mutant α1(I)collagen gene through a glycine-to-cysteine substitution near the C-terminus. Thismutant gene was offered to create lines of transgenic mice via otherwise normalcollagen genes. High-level expression of the mutant transgene was lethal, andexpression at a price 10 percent that of the normal α1(I)genes caused serious development abnormalities.

Collagens Form Diverse Structures

Collagens differ in their capacity to create fibers and also to organize the fibers intonetworks. For example, form II is the significant collagen in cartilage. Its fibrilsare smaller in diameter than form I and are oriented randomly in the viscousproteoglydeserve to matrix. Such rigid macromolecules impart a stamina andcompressibility to the matrix and also allow it to withstand huge deformations inshape. This residential property permits joints to absorb shocks.

Type II fibrils are cross-connected to proteoglycans in the matrix by form IX, acollagen of a different framework (Figure22-16a). Type IX collagen is composed of 2 long triple heliceslinked by a flexible kink. The globular N-terminal domain exhas a tendency from thecomposite fibrils, as does a heparan sulfate molecule, a type of huge, highlycharged polysaccharide (discussed later) that is linked to theα2(IX) chain at the flexible kink. These protrudingnonhelical domains are thshould anchor the fibril to proteoglycans and othercomponents of the matrix. The interrupted triple-helical structure of kind IXcollagen prevents it from assembling into fibrils; instead, these threecollagens associate through fibrils created from various other collagen kinds and also therefore arecalled fibril-connected collagens (see Table 22-3).

Figure 22-16

Interactions of fibrous and nonfibrous collagens. (a) Association of types II and IX collagen in a cartilage matrix.Type II forms fibrils comparable in framework to kind I, through a similar67-nm periodicity, though smaller sized in diameter. Type IX consists of twolong (more...)

Figure 22-24

Structures of miscellaneous glycosaminoglycans, the polysaccharidecomponents of proteoglycans. Each of the four classes of glycosaminoglycans is created bypolymerization of a particular disaccharide and subsequent modificationsconsisting of addition of sulfate (more...)

In many type of connective tissues, form VI collagen is bound to the sides of kind Ifibrils and also might bind them together to create thicker collagen fibers (Figure 22-16b). Type VI collagen isinexplicable in that the molecule is composed of reasonably short triple-helical regionsabout 60 nm lengthy separated by globular domain names about 40 nm long. Fibrils of pureform VI collagen hence offer the impression of beads on a string.

In some places, several ECM components are organized right into a basal lamina, a thin sheetlikeframework. Type IV collagen develops the fundamental fibrous two-dimensional network oautumn basal laminae. Three form IV collagen chains form a 400-nm-long triple helixwith large globular domain names at the C-termini and also smaller sized ones of unknownframework at the N-termini. The helical segment is unexplained in that the Gly-X-Ysequences are interrupted about 24 times with segments that cannot create a triplehelix; these nonhelical areas introduce versatility right into the molecule (Figure 22-17a). Lateral association of theN-terminal areas of 4 type IV molecules returns a characteristic tetramericunit that deserve to be oboffered in the electron microscopic lense (Figure 22-17b). Triple-helical regions from severalmolecules then associate laterally, in a manner similar to fibril formationamong fibrous collagens, to develop branching strands of variable however thindiameters. These interactions, in addition to those between the C-terminalglobular domain names and also the triple helices in nearby kind IV molecules, generatean ircontinuous two-dimensional fibrous netjob-related (Figure 22-17b). We will certainly talk about the various other components of the basallamina and the attributes of this specialized matrix structure in the nextarea.

Figure 22-17

Structure and also assembly of type IV collagen. (a) Schematic diagram of 400-nm-lengthy triple-helical molecule of typeIV collagen. This molecule has actually a noncollagen domajor at theN-terminus and a large globular doprimary at the C-terminus; the triplehelix is interrupted (even more...)




In collagen nomenclature, the collagen kind is in roguy numerals and isenclosed in parentheses.

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