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These precursors not only have the shortamino-terminal signal peptide required to direct the nascent polypeptide tothe ER, but also have, at both their N- and c-terminal ends, additional aminoacids, called propeptides,that are clipped off at a later step of collagen assembly. Moreover, in the lumen of the ER, selected prolines and lysines are hydroxylated to form hydroxyproline and hydroxylysine, respectively, and some of thehydroxy-lysines are glycosylated.
Each pro-cr chain then combines with twoothers to form a hydrogen-bonded, triple-stranded, helical molecule knor,rmasprocollagen.Hydroxylysines and hydroxyprolfnes (Figure 19-64) are infrequently foundin other animal proteins, although hydroxyproline is abundant in some proteins in the plant cell wall. In collagen, the hydroryl groups of these amino acidsare thought to form interchain hydrogen bonds that help stabilize the triplestranded helix. conditions that prevent proline hydroxylation, such as a deficiency of ascorbic acid (vitamin c), have serious consequenc es.ln scuruy, theoften fatal disease caused by a dietary deficiency of vitamin c that was common in sailors until the nineteenth century, the defective pro-cr chains that aresynthesized fail to form a stable triple helix and are immediately degradedwithin the cell, and synthesis of new collagen is inhibited.
In healthy tissues,collagen is continually degraded and replaced (with a turnover time of monthsor years, depending on the tissue). In scurvy, replacement fails, and within afew months, with the gradual loss of the preexisting normal collagen in thematrix, blood vesselsbecome fragile, teeth become loose in their sockets, andwounds ceaseto heal.1187THEEXTRACELLULARMATRIXOFANIMALCONNECTIVETISSUESFigure19-64 HydroxylysineThesemodifiedaminoand hydroxyproline.acidsarecommonin collagen.Theyareformedby enzymesthat act aftermolecules,into procollagenthe lysineand prolinehavebeenincorporatedHOlrl----N-C-C---Hoilc ---CH,ICH:toAfter its Secretion,PropeptidesAre ClippedOff ProcollagenAllowAssemblyof FibrilsAfter secretion, the propeptides of the fibrillar procollagen molecules areremoved by specific proteolltic enz).rnesoutside the cell.
This converts the procollagen molecules to collagen molecules, which assemble in the extracellularspace to form much larger collagen fibrils. The propeptides have at least twofunctions. First, they guide the intracellular formation of the triple-stranded collagen molecules. Second, because they are retained until after secretion, theyprevent the intracellular formation of large collagen fibrils, which could becatastrophic for the cell.The process of fibril formation is driven, in part, by the tendency of the collagen molecules, which are more than a thousandfold less soluble than procollagen molecules, to self-assemble.The fibrils begin to form close to the cell surface, often in deep infoldings of the plasma membrane formed by the fusion ofsecretoryvesicleswith the cell surface.The underlying cortical cytoskeleton caninfluence the sites, rates, and orientation of fibril assembly.\A/henviewed in an electron microscope, collagen fibrils have characteristiccross-striations every 67 nm, reflecting the regularly staggered packing of theindividual collagen molecules in the fibril.
After the fibrils have formed in theextracellular space, they are greatly strengthened by the formation of covalentcross-links between lysine residues of the constituent collagen molecules (Figure 19-65). The types of covalent bonds involved are found only in collagen andelastin. If cross-linking is inhibited, the tensile strength of the fibrils is drasticallyreduced: collagenous tissues become fragile, and structures such as skin, tendons, and blood vesselstend to tear.
The extent and tlpe of cross-linking varyfrom tissue to tissue. Collagen is especially highly cross-linked in the Achillestendon, for example, where tensile strength is crucial.Figure 19-66 summarizes the steps in the synthesis and assembly of collagen fibrils. Given the large number of enzymatic processesinvolved, it is not surprising that there are many human genetic diseasesthat affect fibril formation.Mutations affecting ty?e I collagen cause osteogenesisimlterfecta, characterizedby weak bones that fracture easily. Mutations affecting type II collagen causechondrodysplasias, characterized by abnormal cartilage, which leads to boneand joint deformities.
And mutations affecting type III collagen causeEhlers-Dantos syndrome, characterized by fragile skin and blood vessels andhypermobile joints.IH-C-OHIC H-6\,INHr"h y d r o x y l y s in ein proteinN-CCH,\,/CH,CHIOHh y d r o x y p r oi nl ein proteinthe FibrilsHelpOrganizeFibril-AssociatedCollagensSecretedIn contrast to GAGs,which resist compressiveforces, collagen fibrils form structures that resist tensile forces. The fibrils have various diameters and are organized in different ways in different tissues. In mammalian skin, for example, theyare woven in a wickerwork pattern so that they resist tensile stress in multipledirections; leather consists of this material, suitably preserved.In tendons, collagen fibrils are organized in parallel bundles aligned along the major axis offormedFigurel9-65 Cross-linksbetween modified lysineside chainswithin a collagenfibril.Covalentand intermolecularintramolecularareformed in severalsteps.cross-linksenzymelysylFirst,the extracellularcertainlysinesandoxidasedeaminatesto yieldhighlyreactivehydroxylysines,thenaldehydegroups.Thealdehydesreactspontaneouslyto form covalentbondswith eachotheror with otherMost of thelysinesor hydroxylysines.form betweenthe shortcross-linksnonhelicalsegmentsat eachend of thecollagenmolecules.11 8 8Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixI S Y N T H E SOI SF P R O - gC H A I N2 .
H Y D R O X Y L A T I OONFSELECTEPDROLINESAND LYSINESH:N3 GLYCOSYLATIS E L E C T EHDYHzNCOOHOHS E L F - A S S E M BOLFYT H R E EP R O - aC H A I N S9 . A G G R E G A T I OONFC O L L A G EFNI B R I LTSOF O R MA C O L L A G E FNI B E Rs e c r e t o r yv e s i c l eER/Golgicompartmentp l a s m am e m b r a n e6 SECRETION7 CLEAVAGEOFPROPEPTIDES(A)-r -I10-3008 S E L F . A S S E M B L Yn mI N T OF I B R I LIp r o c o l l a g e nm o l e c u l er__Figure19-66Theintracellularandextracellulareventsin theformationof a collagenfibril.(A)Notethatprocollagenassemblesintocollagenfibrilsin theextracellularspace,oftenwithinlargeinfoldingsin theplasma(notshown).membraneAsoneexampleof howcollagenfibrilscanformorderedarraysin theextracellularspace,theyareshownfurtherassemblingintolargecollagenfibers,whicharevisiblein thelight(B)microscope.Thecovalentcross-linksthatstabilizetheextracellularassemblies(B)Electronareomittedin thispicture.micrographof anegativelystainedcollagenfibrilrevealsitstypicalstriatedappearance.(8,courtesyof RobertHorne.)tension.
In mature bone and in the cornea, they are arranged in orderly plywoodlike layers, with the fibrils in each layer lying parallel to one another butnearly at right anglesto the fibrils in the layers on either side.The same arrangement occurs in tadpole skin (Figure f 9-62).The connective tissue cells themselves determine the size and arrangementof the collagen fibrils. The cells can expressone or more genes for the differenttypes of fibrillar procollagen molecules. But even fibrils composed of the samemixture of fibrillar collagen molecules have different arrangements in differenttissues.How is this achieved?Part of the answer is that cells can regulate the disposition of the collagen molecules after secretion by guiding collagen fibril formation in close association with the plasma membrane (see Figure 1g-66).
Inaddition, cells can influence this organization by secreting, aiong with their fibrillar collagens,different kinds and amounts of other matrix macromolecules. Inparticular, they secretethe fibrous protein fibronectin, as we shall discuss later,and this precedesthe formation of collagen fibrils and helps guide their organization.Fibril-associated collagens, such as types IX and XII collagens,are thoughtto be especially important in this regard.
They differ from fibrillar collagenJinseveral ways.1. Their triple-stranded helical structure is interrupted by one or two shortnonhelical domains, which makes the molecules more flexible than fibrillar collagen molecules.c o l l a g e nf i b r i l1189THEEXTRACELLULARMATRIXOF ANIMALCONNECTIVETISSUES2. They are not cleaved after secretion and therefore retain their propeptides.3. They do not aggregate with one another to form fibrils in the extracellularspace. Instead, they bind in a periodic manner to the surface of fibrilsformed by the fibrillar collagens.Type IX molecules bind to type-ll-collagen-containing fibrils in cartilage, the cornea, and the vitreous of the eye(Figure 19-68), whereas type XII molecules bind to tlpe-I-collagen-containing fibrils in tendons and various other tissues.Fibril-associated collagens are thought to mediate the interactions of collagen fibrils with one another and with other matrix macromolecules to helpdetermine the organization of the fibrils in the matrix.CellsHelpOrganizethe CollagenFibrilsTheySecreteby ExertingTensionon the MatrixCells interact with the extracellular matrix mechanically as well as chemically,and studies in culture suggest that this mechanical interaction can have dramatic effects on the architecture of connective tissue.
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