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Forexample, the heparan sulfate chains of proteoglycans bind to fibroblast growthfactors (FGF|, which (among other effects) stimulate a variety of cell types toproliferate; this interaction oligomerizes the growth factor molecules, enablingthem to cross-link and activate their cell-surface receptors, which are transmembrane tyrosine kinases (see Figure 15-54A). In inflammatory responses,heparan sulfate proteoglycans immobilize secreted chemotactic attractantscalled chemokines (discussed in Chapter 25) on the endothelial surface of ablood vesselat an inflammatory site.This allows the chemokines to remain therefor a prolonged period, stimulating white blood cells to leave the bloodstreamin most casesthe signal moleculesand migrate into the inflamed tissue.\vVhereasbind to the GAG chains of the proteoglycan, this is not always so.
Some membersof the transforming growth factor B QGFD family bind to the core proteins ofseveralmatrix proteoglycans, including decorin; binding to decorin inhibits thegrowth factor activity. Signal molecules (including TGFB) can also bind tofibrous proteins in the matrix. Vascular endothelial growth factor (WGF), forexample, binds to fibronectin.Proteoglycans also bind, and regulate the activities of, other types ofsecreted proteins, including proteolytic enzymes (proteases) and proteaseinhibitors. Thus they play a part in controlling both the assembly and the degradation of other components of the extracellular matrix, including collagen.Cell-5urfaceProteoglycans Act as Co-ReceptorsNot all proteoglycans are secretedcomponents of the extracellular matrix.
Someare integral components of plasma membranes and have their core proteineither inserted acrossthe lipid bilayer or attached to the lipid bilayer by a glycosylphosphatidylinositol (GPI) anchor. Some of these plasma membrane proteoglycans act as co-receptorsthatcollaborate with conventional cell-surfacereceptor proteins. In addition, some conventional receptors have one or more GAGchains and are therefore proteoglycans themselves.Among the best-characterizedplasma membrane proteoglycans are the syndecans, which have a membrane-spanning core protein whose intracellulardomain is thought to interact with the actin cy.toskeletonand with signalingmolecules in the cell cortex.
Syndecansare located on the surface of many typesof cells, including fibroblasts and epithelial cells. In fibroblasts, syndecans canbe found in cell-matrix adhesions, where they modulate integrin function by",184 Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixTable19-6 SomeCommonProteoglycansAggrecan210,000Betaglycan36,000Decorin40,000Perlecan600,000Syndecan-132,000Dally(inDrosophila)60,000chondroitinsulfate+ keratansulfate(in separatechains)chondroitinsulfate/dermatansulfatechondroitinsulfate/dermatansulfateheparansulfate-1302-15cellsurfaceb i n d sT G F Band matrixwidespreadinbinds to type I collagenconnectivetissues fibrilsand TGFBbasallaminaestructuraland filteringchondroitinsulfate+ heparansulfate(in separatechains)heparansulfate1-3cellsurface1-3cellsurface11cartilageinteracting with fibronectin on the cell surface and with cytoskeletal and signaling proteins inside the cell.
Syndecans also bind FGFs and present them toFGF receptor proteins on the same cell. Similarly, another plasma membraneproteoglycan, called betaglycan,binds TGFB and presents it to TGFp receptors.The importance of proteoglycans as co-receptors and as regulators of thedistribution and activity of signal molecules is illustrated by the severedevelopmental defects that can occur when specific proteoglycans are inactivated bymutation.
ln Drosophila, for example, the products of the Dally and Dally-likegenes, coding for members of the glypican family, with heparan sulfate sidechains, are needed for signaling by no less than four of the main signal proteinsthat govern the patterning of the embryo (Wingless, Hedgehog, FGE andDecapentaplegic (Dpp), as discussed in Chapter 22). For some of these signalpathways, mutations in Dally or Dally-like mimic the effects of mutations in thegenes that code for the signal proteins themselves.The structure, function, and location of some of the proteoglycans discussedin this chapter are summarized in Table lg-6.CollagensArethe MajorProteinsof the ExtracellularMatrixThe fibrous proteins are no less important than the proteoglycans as components of the extracellular matrix.
Foremost among them are the collagens, afamily of fibrous proteins found in all multicellular animals. collagens aresecreted in large quantities by connective tissue cells, and in smaller quantitiesby many other cell types. As a major component of skin and bone, they are themost abundant proteins in mammals, where they constitute 2svo of the totalprotein mass.The primary feature of a typical collagen molecule is its long, stiff, triplestranded helical structure, in which three collagen polypeptide chains, called achains, are wound around one another in a ropelike superhelix (Figure 19-62).collagens are extremely rich in proline and glycine, both of which are importantin the formation of the triple-stranded helix.
proline, because of its ring structure, stabilizes the helical conformation in each cr chain, while glycine is regularly spaced at every third residue throughout the central region of the cr chain.Being the smallest amino acid (having only a hydrogen atom as a side chain),glycine allows the three helical cxchains to pack tightly together to form the finalcollagen superhelix.The human genome contains 42 distinct genes coding for different collagenq, chains. Different combinations of these genes are expressedin different tissues.
Although in principle thousands of tlpes of triple-stranded collagenmechanicalsupporUforms largeaggregateswith hyaluronanf u n c t i o ni n b a s a l a m i n ac e l la d h e s i o nb; i n d sF G Fand other growth factorsco-receptorfor win g lessand Decapentaplegics i g n a l i n gp r o t e i n s11 8 5THEEXTRACELLULARMATRIXOFANIMALCONNECTIVETISSUESFigure l9-62 The structure of a typical collagenmolecule.(A)A model ofpart of a singlecollageno chainin whicheachaminoacidis representedby a sphere.Thechainis about 1000aminoacidslong.lt is arrangedasaleft-handedhelix,with threeaminoacidsperturn and with glycineaseverythird amino acid.Therefore,an crchain is composedof a seriesoftripletGly-X-Ysequences,in whichX andY can be any aminoacid(althoughX is commonlyprolineand Y is commonlyhydroxyproline).(B)A modelof part of a collagenmoleculein whichthreecx,chains,eachshown in a differentcolor,are wrappedaround one anotherto form atriple-strandedhelicalrod.Glycineis the only aminoacidsmallenoughtoglycinei,ilr.Tllff;T[:l'T::'^"#T1;::1fliilif:'*::lH""1'i,::1flB.L.Trus.)molecules could be assembled from various combinations of the 42 o chains,only a limited number of triple-helical combinations are possible, and less than40 tlpes of collagen molecules have been found.
TVpe I is by far the most common, being the principal collagen of skin and bone. It belongs to the classof fibrillar collagens, or fibril-forming collagens, which have long ropelike structureswith few or no interruptions. After being secreted into the extracellular space,these collagen molecules assemble into higher-order polyrners called collagenfibrik, which are thin structures (10-300 nm in diameter) many hundreds ofmicrometers long in mature tissues and clearly visible in electron micrographs(Figure 19-63; seealso Figure 19-6I). Collagen fibrils often aggregateinto larger,cablelike bundles, several micrometers in diameter, that are visible in the lightmicroscope as collagenfibers.Collagen types IX and )flI are called ftbril-associated collagens because theydecorate the surface of collagen fibrils.
They are thought to link these fibrils toone another and to other components in the extracellular matrix. Tlpe I! as wehave already seen, is a network-forming collagen, forming a major part of basallaminae, while type VII molecules form dimers that assemble into specializedstructures called anchoringfibrils. Anchoring fibrils help attach the basal laminaof multilayered epithelia to the underlying connective tissue and therefore areespecially abundant in the skin.There are also a number of "collagen-like" proteins, including tlpe X\{I'which has a transmembrane domain and is found in hemidesmosomes, andtype XVIII, which we mentioned earlier as the core protein of a proteoglycan inbasal laminae.Many proteins appear to have evolved by repeated duplications of an original DNA sequence,giving rise to a repetitive pattern of amino acids.
The genesthat encode the crchains of most of the fibrillar collagens provide a good example: they are very large (up to 44 kilobases in length) and contain about 50 exons.Most of the exons are 54, or multiples of 54, nucleotides long, suggesting thatthese collagens originated through multiple duplications of a primordial genetl1pmFigure 19-63 A fibroblast surroundedby collagenfibrils in the connectivetissueof embryonicchickskin' In thiselectronmicrograph,the fibrilsareorganizedinto bundlesthat runat right anglesto oneapproximatelyanother.Therefore,some bundlesarewhereasothersorientedlongitudinally,are seenin crosssection.The collagenfibrilsare producedby the fibroblasts,whichcontainabundantendoplasmicreticulum,where secretedproteinssuch(Fromas collagenare synthesized.C.
Ploetz,E.l.Zycbandand D.E.Birk,1991.WithJ. Struct.Biol.106:73-8'1,permissionfrom Elsevier.)1186Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixTable19-7 SomeTypesof Collagenand Their propertiesFibril-forming(fibrillar)|fibrilllfibrillllfibrilskin,bloodvessels,internalorgansVfibril (withtype l)asfor type Ifibril (withtype ll)lateralassociationwith type ll fibrilssheetlikenetworkasfor type llcartilageanchoringfibrilsnon-fibrillarnon-fibrillarbeneathstratifiedsquamousepitheliahemidesmosomesbasallaminaXlFibril-associated lXNetwork-forminglVVllTransmembrane XVllProteoglycancoreXVlllproteinbone, skin,tendons,ligaments,cornea,severebone defects,fracturesinternalorgans(accountsfor 900/oofbody collagen)cartilage,invertebraldisc,notochord, cartilagedeficiency,dwarfismvitreoushumor of the eyebasallaminafragileskin,loosejoints,bloodproneto rupturevesselsfragileskin,loosejoints,bloodproneto rupturevesselsmyopia,blindnessosteoarthritiskidneydisease(glomerulonephritis),deafnessskinblisterings k i nb l i s t e r i n gmyopia,detachedretina,hydrocephalusNotethattypesl,lV,V,lX,andXlareeachcomposed(distinct,of twoorthreetypesof s chainsnonoverlappingsetsineachcase),whereastypesrr,lll,Vll,Xll,XVll,andXVlllarecomposedof onlyonetypeof o chaineachOnly1Otypesof collagenareshown,butabout27rypesofcollagenand42typesof s chainshavebeenidentifiedin humanscontaining 54 nucleotides and encoding exactly 6 Gly-X-y repeats (see Figure19-62).Table l9-7 provides additional details for some of the collagen types discussed in this chapter.CollagenChainsUndergoa Seriesof Post-TranslationalModificationsIndividual collagen pollpeptide chains are synthesized on membrane-boundribosomes and injected into the lumen of the endoplasmic reticulum (ER) aslarger precursors, called pro-a chains.
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