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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.


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Collagen is the major insoluble fibrous protein in the extracellular matrix and inconnective tworry. In truth, it is the single many abundant protein in the animalkingdom. There are at leastern 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 ofequivalent framework (check out Figure 5-20). TypeIV, in contrast, creates a two-dimensional reticulum; a number of various other forms associatewith fibril-type collagens, linking them to each other or to other matrixcomponents. At one time it was assumed that all collagens were secreted byfibroblasts in connective tproblem, yet we now understand that countless epithelial cellsmake specific kinds of collagens. The assorted collagens and the frameworks they formall serve the very same purpose, to aid tworries withstand stretching.


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The Basic Structural Unit of Collagen Is a Triple Helix

Because its abundance in tendon-wealthy tproblem such as rat tail renders the fibrousform I collagen basic to isolate, it was the initially to be defined. Itsfundamental structural unit is a long (300-nm), thin (1.5-nm-diameter) proteinthat consists of three coiled subunits: 2 α1(I) chains and oneα2(I).* Each chain contains exactly 1050 amino acids wound approximately one another ina characteristic right-handed triple helix (Figure 22-11a). All collagens were inevitably shown to containthree-stranded helical segments of similar structure; the unique properties ofeach kind of collagen are due mostly to segments that interrupt the triple helixand that fold into other kinds of three-dimensional structures.



Figure 22-11

The structure of collagen. (a) The basic 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 inexplicable abundance of3 amino acids: glycine, proline, and hydroxyproline. These amino acids makeup the characteristic repeating motif Gly-Pro-X, wright here X have the right to be any type of amino acid.Each amino acid has a precise feature. The side chain of glycine, an H atom, isthe just one that deserve to fit right 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 surrounding polypeptide help host the threechains together. The fixed angle of the C – Npeptidyl-proline or peptidyl-hydroxyproline bond allows each polypeptide chainto fold right into a helix via a geometry such that 3 polypeptide chains cantwist together to form a three-stranded helix. Interestingly, although the rigidpeptidyl- proline linkeras 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 three-stranded form I collagen molecules pack together side-by-side, formingfibrils via a diameter of 50 – 200 nm. Infibrils, surrounding collagen molecules are disinserted from one one more by 67 nm,around one-quarter of their length (Figure22-11b). This staggered array produces a striated impact that can beviewed in electron micrographs of stained collagen fibrils; the characteristicpattern of bands is repeated about eextremely 67 nm (Figure 22-11c). The distinct properties of the fibrouscollagens — forms I, II, III, andV — are as a result of the ability of the rodprefer triplehelices to develop such side-by-side interactions.

Quick segments at either finish of the collagen chains are of specific importancein the development of collagen fibrils (watch Figure 22-11). These segments execute not assume the triple-helicalcondevelopment and contain the inexplicable amino acid hydroxylysine(watch Figure 3-16). Covalent aldolcross-links develop in between 2 lysine or hydroxylysine residues at the C-terminusof one collagen molecule via 2 comparable residues at the N-terminus of ansurrounding molecule (Figure 22-12). Thesecross-web links stabilize the side-by-side packing of collagen molecules andgenerate a solid fibril.


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Figure 22-12

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


Type I collagen fibrils have actually massive tensile strength; that is, such collagendeserve to be extended without being damaged. These fibrils, around 50 nm in diameterand also several micrometers lengthy, are packed side-by-side in parallel bundles,called collagen fibers, in tendons, wbelow they connect muscleswith bones and have to withstand also substantial forces (Figure 22-13). Gram for gram, type I collagen is stronger thansteel.



Figure 22-13

Electron micrograph of the thick connective tproblem of a chicktendon. Many of the tconcern is inhabited by parallel kind I collagen fibrils,about 50 nm in diameter, seen here in cross section. The cellularcontent of the tissue is exceptionally low.

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

Collagen biosynthesis and assembly complies with the normal pathmeans for a secretedprotein (watch Figure 17-13). The collagenchains are synthesized as much longer precursors calledprocollagens; the prospering peptide chains areco-translationally transported right into the luguys of the turbulent endoplasmic reticulum(ER). In the ER, the procollagen chain undergoes a series of processingreactions (Figure 22-14). First, as withvarious other secreted proteins, glycosylation of procollagen occurs in the rough ER andGolgi complicated. Galactose and glucose residues are included to hydroxylysineresidues, and also long oligosaccharides are included to particular asparagine residues inthe C-terminal propeptide, a segment at the C-terminus of aprocollagen molecule that is absent from mature collagen. (The N-terminal endadditionally has actually a propeptide.) In addition, certain proline and lysine residues in themiddle of the chains are hydroxylated by membrane-bound hydroxylases. Lastly,intrachain disulfide bonds in between the N- and C-terminal propeptide sequencesalign the 3 chains before the triple helix forms in the ER. The centralsections of the chains zipper from C- to N-terminus to create the triplehelix.


Figure 22-14

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


After processing and also assembly of form I procollagen is completed, it is secretedinto the extracellular space. Throughout or adhering to exocytosis, extracellularenzymes, the procollagen peptidases, rerelocate the N-terminal and C-terminalpropeptides. The resulting protein, often referred to as tropocollagen(or sindicate collagen), is composed nearly totally of atriple-stranded helix. Excision of both propeptides allows the collagenmolecules to polymerize into normal fibrils in the extracellular room (seeFigure 22-14). The potentiallycatastrophic assembly of fibrils within the cell does not take place both bereason thepropeptides inhilittle bit fibril formation and because lysyl oxidase, which catalyzesdevelopment of reactive aldehydes, is an extracellular enzyme (see Figure 22-12). As listed over, thesealdehydes spontaneously develop certain covalent cross-links in between twotriple-helical molecules, which stabilizes the staggered selection characteristic ofcollagen molecules and contributes to fibril strength.

Post-translational change ofprocollagen is essential for the formation of mature collagen molecules and theirassembly into fibrils. Defects in this procedure have actually serious consequences, asprehistoric mariners typically skilled. For example, the task of bothprolyl hydroxylases requires an important coaspect, ascorbic acid (vitamin C).In cells deprived of ascorbate, as in the illness scurvy, theprocollagen chains are not hydroxylated sufficiently to develop secure triplehelices at normal body temperature (Figure22-15), nor have the right to they develop normal fibrils. Consequently,nonhydroxylated procollagen chains are degraded within the cell. Without thestructural support of collagen, blood vessels, tendons, and skin end up being vulnerable.A supply of fresh fruit gives enough vitamin C to process procollagenproperly.


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 also loses many of its helical content (even more...)


Mutations in Collagen Reveal Aspects of Its Structure andBiosynthesis

Type I collagen fibrils are supplied as thereinforcing rods in construction of bone. Certain mutations in theα1(I) or α2(I) genes lead toosteogenesis imperfecta, or brittle-bone disease. The mostsevere kind is an autosomal leading, lethal illness bring about fatality in uteroor shortly after birth. Milder develops geneprice a serious crippling condition. Asmight be intended, many type of cases of osteogenesis imperfecta are as a result of deletions oautumn or part of the incredibly long α1(I) gene. However, a singleamino acid readjust is adequate to reason particular creates of this illness. As wehave actually seen, a glycine need to be at eexceptionally third position for the collagen triplehelix to form; mutations of glycine to nearly any kind of various other amino acid aredeleterious, creating poorly created and unstable helices. Since the triplehelix creates from the C- to the N-terminus, mutations of glycine near theC-terminus of the α1(I) chain are usually even more deleteriousthan those close to the N-terminus; the last permit substantial regions of triplehelix to form. Mutant unravelled collagen chains carry out not leave the rough ER offibroblasts (the cells that make a lot of of kind I collagen), or they leave itgradually. As the ER becomes dilated and also expanded, the secretion of various other proteins(e.g., kind III collagen) by these cells additionally is slowed down.

Because each kind I collagen molecule has 2 α1(I) andone α2(I) chains, mutations in theα2(I) chains are much much less damaging. To understand thisallude, take into consideration 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 contrast, if themutation is in the α1(I) chain, 75 percent of the collagenmolecules will certainly have one or 2 mutant α1(I) chains. Intruth, also low expression of a mutant α1(I) gene deserve to bedeleterious, bereason the mutant chains can disrupt the function of wild-typeα1(I) chains as soon as merged through them. To examine suchmutations, experimenters created a mutant α1(I)collagen gene through a glycine-to-cysteine substitution near the C-terminus. Thismutant gene was offered to produce lines of transgenic mice via otherwise normalcollagen genes. High-level expression of the mutant transgene was lethal, andexpression at a rate 10 percent that of the normal α1(I)genes led to severe development abnormalities.


Collagens Form Diverse Structures

Collagens differ in their capability to develop fibers and also to organize the fibers intonetfunctions. For example, kind II is the significant collagen in cartilage. Its fibrilsare smaller in diameter than form I and are oriented randomly in the viscousproteoglyhave the right to matrix. Such rigid macromolecules imcomponent a strength andcompressibility to the matrix and also enable it to withstand huge deformations inshape. This building permits joints to absorb shocks.

Type II fibrils are cross-attached to proteoglycans in the matrix by kind IX, acollagen of a various structure (Figure22-16a). Type IX collagen is composed of 2 lengthy triple heliceslinked by a versatile kink. The globular N-terminal doprimary exoften tends from thecompowebsite fibrils, as does a heparan sulfate molecule, a kind of large, highlycharged polysaccharide (discussed later) that is attached to theα2(IX) chain at the versatile kink. These protrudingnonhelical domain names are thshould anchor the fibril to proteoglycans and also othercomponents of the matrix. The interrupted triple-helical framework of form IXcollagen stays clear of it from assembling right into fibrils; rather, these threecollagens associate through fibrils formed from other collagen forms and also therefore arereferred to as fibril-associated collagens (watch Table 22-3).


Figure 22-16

Interactions of fibrous and nonfibrous collagens. (a) Association of types II and also IX collagen in a cartilage matrix.Type II creates fibrils comparable in framework to type I, with a similar67-nm periodicity, though smaller in diameter. Type IX has 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 details disaccharide and also succeeding modificationsincluding addition of sulfate (more...)


In many connective tproblems, kind VI collagen is bound to the sides of type Ifibrils and also may 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 purekind VI collagen therefore provide the impression of beads on a string.

In some locations, several ECM components are organized into a basal lamina, a thin sheetlikestructure. Type IV collagen forms the fundamental fibrous two-dimensional netjob-related oloss basal laminae. Three kind IV collagen chains create a 400-nm-long triple helixwith big globular domains at the C-termini and smaller sized ones of unknownframework at the N-termini. The helical segment is inexplicable in that the Gly-X-Ysequences are interrupted about 24 times with segments that cannot develop a triplehelix; these nonhelical regions introduce flexibility into the molecule (Figure 22-17a). Lateral association of theN-terminal areas of 4 kind 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 comparable to fibril formationamong fibrous collagens, to create branching strands of variable yet thindiameters. These interactions, along with those between the C-terminalglobular domain names and the triple helices in nearby type IV molecules, generatean ircontinuous two-dimensional fibrous network (Figure 22-17b). We will certainly discuss the other components of the basallamina and also the functions of this specialized matrix framework in the nextarea.


Figure 22-17

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


SUMMARY


Footnotes

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

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