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Thus, in higher plants, as wediscuss later, cellulose (polyglucose) chains are packed tightly together in ribbonlike arrays to form the main component of the cell wall. In insects, crustaceans, and other arthropods, chitin (poly-l/-acetylglucosamine) similarlyforms the main component of the exoskeleton.Fungi, too, make their cell wallsmainly out of chitin. Together, cellulose and chitin are the most abundantbiopolymers on Earth.ag l o b u l a rp r o t e i n( M W 5 0 , 0 0 0 )/f>\.'L)Jg l y c o g e n( M W - 4 0 0 , 0 0 0 )spectrin(MW 460,000)c o l l a g e n( M W 2 9 0 , 0 0 0 )hyaluronan(MW8x106)300nmFigure19-56The relativedimensionsand volumesoccupiedby variousmacromolecules.Severalproteins,aglycogengranule,and a singlehydratedmoleculeof hyaluronanareshown.HyaluronanActsasa SpaceFillerand a Facilitatorof CellM ig r a t i o nD u r i ngT i ssu eMo rp h o g e n e sisand RepairHyaluronan (also called hyaluronic acid or hyaluronate) is the simplest of theGAGs (Figure 19-57).
It consists of a regular repeating sequence of up to 25,000disaccharide units, is found in variable amounts in all tissues and fluids in adultanimals, and is especially abundant in early embryos. Hyaluronan is not tlpicalof the majority of GAGs.In contrast with all of the others, it contains no sulfatedsugars, all its disaccharide units are identical, its chain length is enormous(thousands of sugar monomers), and it is not generally linked covalently to anycore protein.
Moreover, whereas other GAGsare synthesized inside the cell andreleased by exocltosis, hyaluronan is spun out directly from the cell surface byan enzyme complex embedded in the plasma membrane.Hyaluronan is thought to have a role in resisting compressive forces in tissues and joints. It is also important as a space filler during embryonic development, where it can be used to force a change in the shape of a structure, as asmall quantity expands with water to occupy a large volume (seeFigure 19-56).Hyaluronan synthesizedlocally from the basal side of an epithelium can deformthe epithelium by creating a cell-free space beneath it, into which cells subsequently migrate. In the developing heart, for example, hyaluronan slmthesishelps in this way to drive formation of the valves and septa that separate theheart's chambers.
similar processes occur in several other organs. \Mhen cellCH,OHt^F"\--N-acetylglucosaminet)t/lllNHCOCHsOHNHCOCHTg l u c u r o n i ca c i dr e p e a t i n gd i s a c c h a r i d eOHFigure19-57 The repeatingdisaccharidesequencein hyaluronan,a relativelysimpleGAG.Thisubiquitousmoleculeinvertebratesconsistsof a singlelong chainof up to 25,000sugarmonomers.Notetheabsenceof sulfategroups.11 8 1THEEXTRACELLULARMATRIXOF ANIMALCONNECTIVETISSUESmigration ends, the excess hyaluronan is generally degraded by the enzymehyaluronida.se.Hyaluronan is also produced in large quantities during woundhealing, and it is an important constituent of joint fluid, in which it serves as alubricant.Many of the functions of hyaluronan depend on specific interactions withother molecules, including both proteins and proteoglycans. Some of thesemolecules that bind to hyaluronan are constituents of the extracellular matrix,while others are integral components of cell surfaces.ProteoglycansLinkedtoAreComposedof GAGChainsCovalentlya CoreProteinExcept for hyaluronan, all GAGs are covalently attached to protein as proteoglycans, which are produced by most animal cells.
Membrane-bound ribosomesmake the polypeptide chain, or core protein, of a proteoglycan, which is thenthreaded into the lumen of the endoplasmic reticulum. The polysaccharidechains are mainly assembled on this core protein in the Golgi apparatus beforedelivery to the exterior of the cell by exocytosis.First, a special linkage tetrasaccharideis attached to a serine side chain on the core protein to serve as a primerfor polysaccharide growth; then, one sugar at a time is added by specific glycosyl transferases(Figure 19-58). \A/hile still in the Golgi apparatus, many of thepolymerized sugars are covalently modified by a sequential and coordinatedseries of reactions.
Epimerizations alter the configuration of the substituentsaround individual carbon atoms in the sugar molecule; sulfations increase thenegative charge.Proteoglycansare usually clearly distinguished from other glycoproteins bythe nature, quantity, and arrangement of their sugar side chains. By definition,at least one of the sugar side chains of a proteoglycan must be a GAG.\Vhereasglycoproteins contain l-607o carbohydrate by weight, and usually only a fewpercent, in the form of numerous relatively short, branched oligosaccharidechains, proteoglycans can contain as much as 95% carbohydrate by weight,mostly in the form of long, unbranched GAG chains, each typically about B0 sugars long.In principle, proteoglycans have the potential for almost limitless heterogeneity.Even a single tlpe of core protein can carry highly variable numbers andtlpes of attached GAG chains.
Moreover, the underlying repeating sequence ofdisaccharides in each GAG can be modified by a complex pattern of sulfategroups. The core proteins, too, are diverse, though many of them share somecharacteristic domains such as the LINK domain, involved in binding to GAGs.Proteoglycanscan be huge. The proteoglycan aggrecan,for example, whichis a major component of cartilage,has a mass of about 3 x 106daltons with over100 GAG chains. Other proteoglycans are much smaller and have only l-10 GAGchains; an example is decorin, which is secreted by fibroblasts and has a single..()serineH-(.LJ\(ll,()-x y l o s e-galactose -galactose -Ilinktetrasaccharide\\coreprotelnglucuroniclFigure19-58ThelinkagebetweenaGAGchainand its core Proteinin aproteoglycanmolecule,A specificlinkon aisfirstassembledtetrasaccharideit isserinesidechain.In mostcases,unclearhow the particularserineisbut it seemsthat a specificlocalselected,of the polypeptidechain,conformationofratherthan a specificlinearsequenceThe restof theaminoacids,is recognized.GAGchain,consistingmainlyof aunit,isthenrepeatingdisaccharidewith one sugarbeingaddedsynthesized,at a time.In chondroitinsulfate,theis composedof o-glucuronicdisaccharideinacidand N-acetyl-o-galactosamine;(orheparansulfate,it is o-glucosamineacid)and N-acetyl-DL-iduronicglucosamine;in keratansulfate,it isand N-acetyl-o-glucosamine.o-galactose1182Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixDECORIN(MW - 40,000)AGGRECAN(MW-3x106)corep r o t e i n\RIBONUCLEASE(MW - 15,000)s h o r t ,b r a n c h e doligosaccharides i d ec h a i n - - -Xj i\tr/\/\/p o l y p e p t i d ec h a i n1 0 0n mGAG chain (Figure f 9-59).
Decorin binds to collagen fibrils and regulates fibrilassembly and fibril diameter; mice that cannot make decorin have fragile skinthat has reduced tensile strength. The GAGs and proteoglycans of these variousty?es can associate to form even larger polyrneric complexes in the extracellularmatrix. Molecules of aggrecan,for example, assemblewith hyaluronan in cartilage matrix to form aggregatesthat are as big as a bacterium (FigUre fg-60).Moreover,besidesassociatingwith one another, GAGsand proteoglycansassociate with fibrous matrix proteins such as collagen and with protein meshworkssuch as the basal lamina, creating extremely complex composites (Figure f 9-6f ).ProteoglycansCanRegulatethe Activitiesof SecretedProteinsProeteoglycans are as diverse in function as they are in chemistry and structure.
Their GAG chains, for example, can form gels of varying pore size andcharge density; one possible function, therefore, is to serve as selective sievest utFigure19-59 Examplesof a small(decorin)and a large(aggrecan)proteoglycanfound in the extracellularmatrix.The figure comparesthesetwoproteoglycanswith a typicalsecretedglycoproteinmolecule,pancreaticribonucleaseB.All threearedrawntoThecoreproteinsof both aggrecanscale.and decorincontainoligosaccharidechainsaswell asthe GAGchains,butthesearenot shown.Aggrecantypicallyconsistsof about 100chondroitinsulfatechainsand about 30 keratansulfatechainslinkedto a serine-richcoreproteinof almost3000aminoacids.Decorin"decorates"the surfaceof collaqenfibrils.henceits name.-a g g r e c a na g g r e g a t eh y aIu r o n a nmolecule-/\-\_--\_>-<'><-chondroitinsulfate1ttFigure19-60An aggrecanaggregatefrom fetal bovinecartilage.(A)An electronmicrographof an aggrecanaggregareshadowedwith platinum.Manyfreeaggrecanmoleculesarealsovisible.(B)A drawingof the giantaggrecanaggregateshownin (A).lt consistsof about 100aggrecanmonomers(eachlikethe one shownin Figure19-59)noncovalentlyboundthroughthe N-terminaldomainof the coreproteinto a singlehyaluronanchain.A link proteinbindsboth to the coreproteinof the proteoglycanand to the hyaluronanchain,therebystabilizingthe aggregate.The link proteinsare membersof a familyof hyaluronan-bindingproteins,someof whicharecell-surfaceproteins.The molecularweightof suchacomplexcan be 108or more,and it occupiesa volumeequivalentto that of a bacterium,which is about2; 16-12.r3.(A,courtesyof LawrenceRosenberg.)THEEXTRACELLULARMATRIXOFANIMALCONNECTIVETISSUES11 8 3in theFigure19-61 Proteoglycansextracellularmatrix of rat cartilage.Thetissuewasrapidlyfrozenat -196'C,andfixedand stainedwhile stillfrozen(aprocesscalledfreezesubstitution)topreventthe GAGchainsfrom collapsing.theIn this electronmicrograph,proteoglycanareseento formmoleculesa fine filamentousnetworkin whichasinglestriatedcollagenfibrilisembedded.The moredarklystainedpartsmoleculesaretheof the proteoglycancoreproteins;the faintlystainedthreadsfromarethe GAGchains.(ReproducedE.B.Hunzikerand R.K.Schenk,J.
CellBiol.98:277-282, 1984.With permissionfromUniversityPress.)The Rockefeller05[mto regulate the traffic of molecules and cells according to their size and charge,as in the thick basal lamina of the kidney glomerulus (seep. 1167).Proteoglycanshave an important role in chemical signaling between cells.They bind various secretedsignal molecules, such as certain protein growth factors-controlling their diffusion through the matrix, their range of action, andtheir lifetime, as well as enhancing or inhibiting their signaling activity.
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