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Lodish H, Berk A, Zipursky SL, et al. Molecular cabinet 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 also inconnective tissue. In fact, that is the single most plentiful protein in the animalkingdom. There space at the very least 16 varieties of collagen, but80 – 90 percent the the collagen in the human body consistsof varieties I, II, and also III (Table 22-3).These collagen molecules load together to type long slim fibrils ofsimilar structure (see figure 5-20). TypeIV, in contrast, creates a two-dimensional reticulum; several other types associatewith fibril-type collagens, linking them come each other or to various other matrixcomponents. At one time it was assumed that every collagens to be secreted byfibroblasts in connective tissue, however we now understand that countless epithelial cellsmake certain varieties of collagens. The miscellaneous collagens and also the structures they formall serve the very same purpose, to assist tissues stand up to stretching.


The simple Structural Unit the Collagen Is a Triple Helix

Because its diversity in tendon-rich organization such as rat tail makes the fibroustype ns collagen basic to isolate, it was the an initial to it is in characterized. Itsfundamental structural unit is a long (300-nm), thin (1.5-nm-diameter) proteinthat consists of 3 coiled subunits: two α1(I) chains and also oneα2(I).* every chain includes precisely 1050 amino acids wound around one another ina properties right-handed triple helix (Figure 22-11a). Every collagens to be eventually shown to containthree-stranded helical segment of comparable structure; the distinct properties ofeach form of collagen are due greatly to segments the interrupt the triple helixand that fold into other kinds 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 structure of collagen occurs from an unusual abundance ofthree amino acids: glycine, proline, and hydroxyproline. These amino acids makeup the properties repeating motif Gly-Pro-X, where X can be any kind of amino acid.Each amino acid has actually a precise function. The side chain that glycine, an H atom, isthe just one that have the right to fit into the crowded facility of a three-stranded helix.Hydrogen binding linking the peptide link NH that a glycine residue through a peptidecarbonyl (C═O) group in an nearby polypeptide assist hold the threechains together. The fixed angle the the C – Npeptidyl-proline or peptidyl-hydroxyproline bond enables each polypeptide chainto fold into a helix v a geometry such that three polypeptide chain cantwist together to type a three-stranded helix. Interestingly, back the rigidpeptidyl- proline linkages disrupt the packing of amino mountain in an αhelix, they stabilize the strict three-stranded collagen helix.

Collagen Fibrils form by Lateral interaction of Triple Helices

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

Short segment at either end of the collagen chains room of details importancein the formation of collagen fibrils (see number 22-11). These segments carry out not assume the triple-helicalconformation and also contain the unexplained amino acid hydroxylysine(see number 3-16). Covalent aldolcross-links type between 2 lysine or hydroxylysine residues at the C-terminusof one collagen molecule through two comparable 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.


Figure 22-12

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

Type i collagen fibrils have substantial tensile strength; the is, such collagencan be stretched without gift broken. This fibrils, around 50 nm in diameterand number of micrometers long, room packed side-by-side in parallel bundles,called collagen fibers, in tendons, wherein they attach muscleswith bones and also must withstand massive forces (Figure 22-13). Gram for gram, kind I collagen is more powerful thansteel.

Figure 22-13

Electron micrograph of the dense connective tissue of a chicktendon. Most of the organization is lived in by parallel type I collagen fibrils,about 50 nm in diameter, seen below in cross section. The cellularcontent of the organization is really low.

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

Collagen biosynthesis and assembly follows the normal pathway for a secretedprotein (see figure 17-13). The collagenchains are synthesized as longer precursors calledprocollagens; the growing peptide chain areco-translationally transported into the lumen that the stormy endoplasmic reticulum(ER). In the ER, the procollagen chain experience a collection of processingreactions (Figure 22-14). First, as withother secreted proteins, glycosylation of procollagen occurs in the stormy ER andGolgi complex. Galactose and glucose residues are included to hydroxylysineresidues, and also long oligosaccharides are included to certain asparagine residual water inthe C-terminal propeptide, a segment at the C-terminus of aprocollagen molecule the is missing from maturation collagen. (The N-terminal endalso has a propeptide.) In addition, details proline and lysine residual water in themiddle of the chains space hydroxylated by membrane-bound hydroxylases. Lastly,intrachain de defiders bonds between the N- and also C-terminal propeptide sequencesalign the 3 chains before the triple helix creates in the ER. The centralportions that the chains zipper from C- come N-terminus to kind the triplehelix.

Figure 22-14

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

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

Post-translational change ofprocollagen is an essential for the development of tires collagen molecules and also theirassembly into fibrils. Defects in this procedure have severe consequences, asancient mariners typically experienced. Because that example, the task of bothprolyl hydroxylases requires an essential cofactor, ascorbic mountain (vitamin C).In cells deprived the ascorbate, together in the disease scurvy, theprocollagen chains room not hydroxylated saturated to type stable triplehelices at regular body temperature (Figure22-15), nor deserve to they kind normal fibrils. Consequently,nonhydroxylated procollagen chains room degraded within the cell. There is no thestructural support of collagen, blood vessels, tendons, and skin end up being fragile.A supply of new fruit provides adequate vitamin C to process procollagenproperly.

Figure 22-15

Denaturation that collagen comprise a regular content ofhydroxyproline and also of abnormal collagen containing nohydroxyproline. Without hydrogen bonds between hydroxyproline residues, the collagenhelix is unstable and also loses many of that is helical content (more...)

Mutations in Collagen Reveal elements of Its framework andBiosynthesis

Type ns collagen fibrils are used as thereinforcing rods in building of bone. Particular mutations in theα1(I) or α2(I) genes lead toosteogenesis imperfecta, or brittle-bone disease. The mostsevere kind is one autosomal dominant, lethal condition resulting in fatality in uteroor shortly after birth. Milder forms generate a significant crippling disease. Asmight it is in expected, many situations of osteogenesis imperfecta are due to deletions ofall or part of the very long α1(I) gene. However, a singleamino acid change is adequate to cause specific forms the this disease. Together wehave seen, a glycine have to be at every third position because that the collagen triplehelix come form; mutations the glycine to nearly any other amino acid aredeleterious, creating poorly formed and also unstable helices. Due to the fact that the triplehelix forms from the C- come the N-terminus, mutations the glycine near theC-terminus of the α1(I) chain room usually an ext deleteriousthan those close to the N-terminus; the latter permit considerable regions of triplehelix to form. Mutant unfolded collagen chains carry out not leave the stormy ER offibroblasts (the cells that make most of kind I collagen), or they leaving itslowly. Together the ER i do not care dilated and expanded, the secretion of other proteins(e.g., form III collagen) by these cells additionally is slowed down.

Because each kind I collagen molecule contains two α1(I) andone α2(I) chains, mutations in theα2(I) chains are much much less damaging. To know thispoint, think about that in a heterozygote to express one wild-type and one mutantα2(I) protein, 50 percent that the collagen moleculeswill have actually the abnormal α2(I) chain. In contrast, if themutation is in the α1(I) chain, 75 percent the the collagenmolecules will have actually one or 2 mutant α1(I) chains. Infact, even low expression of a mutant α1(I) gene can bedeleterious, since the mutant chains can disrupt the role of wild-typeα1(I) chains when combined with them. To examine suchmutations, experimenters constructed a mutant α1(I)collagen gene with a glycine-to-cysteine substitution close to the C-terminus. Thismutant gene was provided to create lines of transgenic mice v otherwise normalcollagen genes. High-level expression of the mutant transgene to be lethal, andexpression at a price 10 percent that of the common α1(I)genes brought about severe expansion abnormalities.

Collagens type Diverse Structures

Collagens different in their ability to form fibers and also to theorem the fibers intonetworks. Because that example, kind II is the significant collagen in cartilage. That is fibrilsare smaller in diameter than type I and are oriented randomly in the viscousproteoglycan matrix. Together rigid macromolecules impart a stamin andcompressibility come the procession and permit it come resist big deformations inshape. This property permits joints to absorb shocks.

Type II fibrils room cross-linked come proteoglycans in the matrix by type IX, acollagen that a various structure (Figure22-16a). Form IX collagen is composed of two long triple helicesconnected through a versatile kink. The globular N-terminal domain extends native thecomposite fibrils, together does a heparan sulfate molecule, a type of large, highlycharged polysaccharide (discussed later) the is attached to theα2(IX) chain in ~ the versatile kink. This protrudingnonhelical domains are thought to anchor the fibril come proteoglycans and othercomponents of the matrix. The interrupted triple-helical framework of type IXcollagen avoids it from assembling into fibrils; instead, these threecollagens associate with fibrils created from other collagen varieties and hence arecalled fibril-associated collagens (see Table 22-3).

Figure 22-16

Interactions of fibrous and nonfibrous collagens. (a) association of species II and IX collagen in a cartilage matrix.Type II develops fibrils similar in structure to form I, v a similar67-nm periodicity, though smaller in diameter. Kind IX contains twolong (more...)

Figure 22-24

Structures of miscellaneous glycosaminoglycans, the polysaccharidecomponents of proteoglycans. Each of the 4 classes the glycosaminoglycans is developed bypolymerization of a certain disaccharide and also subsequent modificationsincluding addition of sulfate (more...)

In numerous connective tissues, form VI collagen is bound to the sides of type Ifibrils and also may bind them with each other to kind thicker collagen yarn (Figure 22-16b). Kind VI collagen isunusual in the the molecule consists of reasonably short triple-helical regionsabout 60 nm lengthy separated through globular domains around 40 nm long. Fibrils the puretype by means of collagen thus provide the impression of beads ~ above a string.

In part places, numerous ECM materials are organized right into a basal lamina, a thin sheetlikestructure. Kind IV collagen creates the straightforward fibrous two-dimensional network ofall basal laminae. Three type IV collagen chains type a 400-nm-long triple helixwith big globular domain names at the C-termini and also smaller people of unknownstructure at the N-termini. The helical segment is unusual in that the Gly-X-Ysequences are interrupted around 24 times v segments the cannot kind a triplehelix; these nonhelical areas introduce versatility into the molecule (Figure 22-17a). Lateral combination of theN-terminal areas of four kind IV molecules yields a characteristic tetramericunit that can be observed in the electron microscopic lense (Figure 22-17b). Triple-helical areas from severalmolecules climate associate laterally, in a manner comparable to fibril formationamong fibrous collagens, to form branching strands of variable yet 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 contents of the basallamina and also the functions of this committed matrix structure in the nextsection.

Figure 22-17

Structure and assembly of kind IV collagen. (a) Schematic chart of 400-nm-long triple-helical molecule the typeIV collagen. This molecule has a noncollagen domain at theN-terminus and also a large globular domain at the C-terminus; the triplehelix is interrupted (more...)




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

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