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Lodish H, Berk A, Zipursky SL, et al. Molecular cell Biology. Fourth edition. Brand-new York: W. H. Freeman; 2000.


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Collagen is the significant insoluble fibrous protein in the extracellular matrix and inconnective tissue. In fact, that is the solitary most numerous protein in the animalkingdom. There space at the very least 16 varieties of collagen, but80 – 90 percent of the collagen in the body consistsof types I, II, and III (Table 22-3).These collagen molecules load together to type long slim fibrils ofsimilar structure (see number 5-20). TypeIV, in contrast, creates a two-dimensional reticulum; several other species associatewith fibril-type collagens, linking them come each various other or to other matrixcomponents. At one time it was thought that every collagens to be secreted byfibroblasts in connective tissue, yet we now know that many epithelial cellsmake certain types of collagens. The assorted collagens and the structures they formall serve the same purpose, to help tissues withstand stretching.


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The straightforward Structural Unit that Collagen Is a Triple Helix

Because its abundance in tendon-rich tissue such together rat tail makes the fibroustype ns collagen basic to isolate, it was the very first to be characterized. Itsfundamental structural unit is a long (300-nm), thin (1.5-nm-diameter) proteinthat is composed of 3 coiled subunits: two α1(I) chains and also oneα2(I).* every chain contains precisely 1050 amino mountain wound about one an additional ina characteristics right-handed triple helix (Figure 22-11a). All collagens were eventually presented to containthree-stranded helical segment of comparable structure; the distinctive properties ofeach type of collagen room due greatly to segments that interrupt the triple helixand the fold right into other type of three-dimensional structures.



Figure 22-11

The framework of collagen. (a) The an easy structural unit is a triple-stranded helical molecule.Each triple-stranded collagen molecule is 300 nm long. (b) Infibrous collagen, collagen molecules fill together next by side.Adjacent molecules are displaced (more...)


The triple-helical framework of collagen occurs from an unexplained abundance ofthree amino acids: glycine, proline, and hydroxyproline. These amino mountain makeup the properties repeating motif Gly-Pro-X, where X can be any type of amino acid.Each amino acid has actually a precise function. The side chain the glycine, an H atom, isthe only one that deserve to fit right into the crowded center of a three-stranded helix.Hydrogen bonds linking the peptide link NH the a glycine residue v a peptidecarbonyl (C═O) team in an nearby polypeptide aid hold the threechains together. The solved angle of the C – Npeptidyl-proline or peptidyl-hydroxyproline bond allows each polypeptide chainto fold into a helix through a geometry such that three polypeptide chains cantwist with each other to kind a three-stranded helix. Interestingly, although the rigidpeptidyl- proline linkages disrupt the packing of amino acids in one αhelix, they stabilize the rigid three-stranded collagen helix.


Collagen Fibrils form by Lateral interaction of Triple Helices

Many three-stranded form I collagen molecules load together side-by-side, formingfibrils through a diameter of 50 – 200 nm. Infibrils, adjacent collagen molecules space displaced indigenous one an additional by 67 nm,about one-quarter of their length (Figure22-11b). This staggered variety produces a striated impact that can beseen in electron micrographs of stained collagen fibrils; the characteristicpattern of bands is repeated around every 67 nm (Figure 22-11c). The distinct properties the the fibrouscollagens — types I, II, III, andV — are as result of the ability of the rodlike triplehelices to form such side-by-side interactions.

Short segment at either end of the collagen chains are of particular importancein the development of collagen fibrils (see figure 22-11). These segments execute not assume the triple-helicalconformation and also contain the unusual amino mountain hydroxylysine(see figure 3-16). Covalent aldolcross-links type between 2 lysine or hydroxylysine residual water at the C-terminusof one collagen molecule through two similar residues at the N-terminus the anadjacent molecule (Figure 22-12). Thesecross-links stabilize the side-by-side packing of collagen molecule andgenerate a strong fibril.


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Figure 22-12

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


Type i collagen fibrils have enormous tensile strength; that is, together collagencan be extended without being broken. These fibrils, approximately 50 nm in diameterand several micrometers long, are packed side-by-side in parallel bundles,called collagen fibers, in tendons, wherein they connect muscleswith bones and also must withstand substantial forces (Figure 22-13). Gram for gram, form I collagen is stronger thansteel.



Figure 22-13

Electron micrograph of the thick connective organization of a chicktendon. Most of the tissue is populated by parallel kind I collagen fibrils,about 50 nm in diameter, seen right here in overcome section. The cellularcontent of the organization is very low.

Assembly that Collagen Fibers starts in the ER and Is Completed exterior theCell

Collagen biosynthesis and assembly adheres to the regular pathway because that a secretedprotein (see number 17-13). The collagenchains are synthesized as longer precursors calledprocollagens; the cultivation peptide chain areco-translationally transported right into the lumen the the stormy endoplasmic reticulum(ER). In the ER, the procollagen chain undergoes a series of processingreactions (Figure 22-14). First, as withother secreted proteins, glycosylation of procollagen occurs in the stormy ER andGolgi complex. Galactose and glucose residual water are included to hydroxylysineresidues, and long oligosaccharides are added to particular asparagine residues inthe C-terminal propeptide, a segment in ~ the C-terminus the aprocollagen molecule that is absent from maturation collagen. (The N-terminal endalso has a propeptide.) In addition, certain proline and also lysine residues in themiddle the the chains room hydroxylated by membrane-bound hydroxylases. Lastly,intrachain de defiders bonds in between the N- and also C-terminal propeptide sequencesalign the 3 chains prior to the triple helix creates in the ER. The centralportions of the chain zipper from C- to N-terminus to kind the triplehelix.


Figure 22-14

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


After processing and assembly of form I procollagen is completed, it is secretedinto the extracellular space. During or following exocytosis, extracellularenzymes, the procollagen peptidases, eliminate the N-terminal and also C-terminalpropeptides. The resulting protein, often dubbed tropocollagen(or merely collagen), consists practically entirely that atriple-stranded helix. Excision of both propeptides allows the collagenmolecules to polymerize into normal fibrils in the extracellular space (seeFigure 22-14). The potentiallycatastrophic assembly of fibrils within the cell does not occur both because thepropeptides inhibit fibril formation and because lysyl oxidase, which catalyzesformation the reactive aldehydes, is an extracellular enzyme (see figure 22-12). As listed above, thesealdehydes spontaneously kind specific covalent cross-links in between twotriple-helical molecules, i m sorry stabilizes the staggered selection characteristic ofcollagen molecules and also contributes to fibril strength.

Post-translational change ofprocollagen is vital for the formation of mature collagen molecules and also theirassembly right into fibrils. Defects in this process have major consequences, asancient mariners commonly experienced. For example, the activity of bothprolyl hydroxylases requires vital cofactor, ascorbic acid (vitamin C).In cells deprived the ascorbate, as in the disease scurvy, theprocollagen chains are not hydroxylated saturated to kind stable triplehelices at normal body temperature (Figure22-15), nor deserve to they form normal fibrils. Consequently,nonhydroxylated procollagen chains space degraded in ~ the cell. There is no thestructural assistance of collagen, blood vessels, tendons, and also skin become fragile.A supply of new fruit provides enough vitamin C to procedure procollagenproperly.


Figure 22-15

Denaturation of collagen containing a regular content ofhydroxyproline and of abnormal collagen comprise nohydroxyproline. There is no hydrogen bonds between hydroxyproline residues, the collagenhelix is unstable and loses many of that is helical contents (more...)


Mutations in Collagen Reveal elements of Its framework andBiosynthesis

Type ns collagen fibrils are used as thereinforcing rods in building and construction of bone. Particular mutations in theα1(I) or α2(I) genes lead toosteogenesis imperfecta, or brittle-bone disease. The mostsevere type is an autosomal dominant, lethal an illness resulting in fatality in uteroor quickly after birth. Milder develops generate a severe crippling disease. Asmight it is in expected, many situations of osteogenesis imperfecta are because of deletions ofall or component of the really long α1(I) gene. However, a singleamino acid readjust is adequate to cause details forms the this disease. Together wehave seen, a glycine should be in ~ every third position because that the collagen triplehelix to form; mutations of glycine to nearly any various other amino acid aredeleterious, creating poorly formed and also unstable helices. Due to the fact that the triplehelix develops from the C- come the N-terminus, mutations that glycine near theC-terminus that the α1(I) chain room usually much more deleteriousthan those close to the N-terminus; the last permit substantial regions that triplehelix come form. Mutant unravelled collagen chains do not leaving the rough ER offibroblasts (the cells the make many of form I collagen), or they leaving itslowly. As the ER becomes dilated and also expanded, the cheap of other proteins(e.g., type III collagen) by these cells likewise is slowed down.

Because each form I collagen molecule includes two α1(I) andone α2(I) chains, mutations in theα2(I) chains room much much less damaging. To understand thispoint, think about that in a heterozygote expressing one wild-type and one mutantα2(I) protein, 50 percent the the collagen moleculeswill have actually the abnormal α2(I) chain. In contrast, if themutation is in the α1(I) chain, 75 percent of the collagenmolecules will have actually one or two mutant α1(I) chains. Infact, also low expression the a mutant α1(I) gene have the right to bedeleterious, due to the fact that the mutant chains have the right to disrupt the function of wild-typeα1(I) chains when an unified with them. To study suchmutations, experimenters constructed a mutant α1(I)collagen gene with a glycine-to-cysteine substitution close to the C-terminus. Thismutant gene was supplied to create lines of transgenic mice with otherwise normalcollagen genes. High-level expression that the mutant transgene was lethal, andexpression at a price 10 percent that of the normal α1(I)genes led to severe growth abnormalities.


Collagens type Diverse Structures

Collagens differ in their capacity to kind fibers and also to organize the fibers intonetworks. Because that example, form II is the significant collagen in cartilage. That fibrilsare smaller in diameter than kind I and also are oriented randomly in the viscousproteoglycan matrix. Together rigid macromolecules send a toughness andcompressibility to the procession and enable it to resist big deformations inshape. This property enables joints to absorb shocks.

Type II fibrils are cross-linked come proteoglycans in the matrix by form IX, acollagen of a various structure (Figure22-16a). Form IX collagen consists of two lengthy triple helicesconnected by a functional kink. The globular N-terminal domain extends from thecomposite fibrils, together does a heparan sulfate molecule, a form of large, highlycharged polysaccharide (discussed later) that is attached to theα2(IX) chain at the functional kink. These protrudingnonhelical domain names are thought to anchor the fibril come proteoglycans and othercomponents of the matrix. The interrupted triple-helical framework of form IXcollagen prevents it native assembling right into fibrils; instead, these threecollagens associate through fibrils formed from other collagen types and hence arecalled fibril-associated collagens (see Table 22-3).


Figure 22-16

Interactions the fibrous and also nonfibrous collagens. (a) combination of types II and also IX collagen in a cartilage matrix.Type II develops fibrils similar in structure to kind I, v a similar67-nm periodicity, though smaller sized in diameter. Type IX consists of twolong (more...)


Figure 22-24

Structures of various glycosaminoglycans, the polysaccharidecomponents of proteoglycans. Each of the four classes the glycosaminoglycans is developed bypolymerization of a details disaccharide and subsequent modificationsincluding enhancement of sulfate (more...)


In numerous connective tissues, type VI collagen is bound to the political parties of form Ifibrils and may tie them with each other to form thicker collagen fibers (Figure 22-16b). Kind VI collagen isunusual in the the molecule is composed of relatively short triple-helical regionsabout 60 nm long separated through globular domains about 40 nm long. Fibrils the puretype through collagen thus give the impression that beads ~ above a string.

In some places, number of ECM materials are organized right into a basal lamina, a slim sheetlikestructure. Type IV collagen forms the straightforward fibrous two-dimensional network ofall basal laminae. Three kind IV collagen chains type a 400-nm-long triple helixwith large globular domain names at the C-termini and also smaller people of unknownstructure at the N-termini. The helical segment is unexplained in the the Gly-X-Ysequences room interrupted around 24 times v segments the cannot form a triplehelix; this nonhelical regions introduce versatility into the molecule (Figure 22-17a). Lateral association of theN-terminal regions of four type IV molecules returns a properties tetramericunit that can be it was observed in the electron microscopic lense (Figure 22-17b). Triple-helical areas from severalmolecules then associate laterally, in a manner similar to fibril formationamong fibrous collagens, to form branching strands of variable however thindiameters. This interactions, along with those between the C-terminalglobular domains and also the triple helices in adjacent form IV molecules, generatean rarely often rare two-dimensional fibrous network (Figure 22-17b). Us will discuss the other components of the basallamina and also the functions of this dedicated matrix framework in the nextsection.


Figure 22-17

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


SUMMARY


Footnotes

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In collagen nomenclature, the collagen form is in roman numerals and also isenclosed in parentheses.

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