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In the skin, for example, theepithelial outer layer-the epidermis-depends on the strength of the basallamina to keep it attached to the underlying connective tissue-the dermis. Inpeople with genetic defects in certain basal lamina proteins or in a special typeof collagen that anchors the basal lamina to the underlying connective tissue,the epidermis becomes detached from the dermis.
This causes a blistering diseasecalled junctional epidermolysisbullosa, a severeand sometimes lethal condition.Lamininls a PrimaryComponentof the BasalLaminaThe basal lamina is slmthesized by the cells on each side of it: the epithelial cellscontribute one set of basal lamina components, while cells of the under$ing bedof connective tissue (called the stroma, Greek for "bedding") contribute anotherset (Figure f 9-40). Like other extracellular matrices in animal tissues, the basallamina consists of two main classesof extracellular macromolecules: (l) fibrousproteins (usually glycoproteins, which have short oligosaccharide side chainsattached) and (2) polysaccharide chains of the type called glycosaminoglycans(GAGI),which are usually found covalently linked to specific coreproteins to formproteoglycans (Figure f 9-4f ).
In a later section, we shall discuss these two largeand varied classesof matrix molecules in greater detail. We introduce them herethrough the special subset that are found in basal laminae.Although the precise composition of the mature basal lamina varies fromtissue to tissue and even from region to region in the same lamina, it typicallycontains the glycoproteins laminin, type IV collagen, and, nidogen, along withthe proteoglycan perlecan Together with these key components, present in thebasal laminae of virtually all animals from jellfish to mammals, it holds in itsmeshes, or is closely associated with, various other molecules.
These includecollagen XWII (an atypical member of the collagen family, forming the core protein of a proteoglycan) and fibronectin, afibrous protein important in the adhesion of connective-tissue cells to matrix.The laminin is thought to be the primary organizer of the sheet structure,and early in development, basal laminae consist mainly of laminin molecules.Laminin-l (classicallaminin) is a large, flexible protein composed of three verye p i t h e l i a lc e l l sbasal aminac o rIa g e n1 0l r .Figure19-40The basallaminain thecorneaof a chickembryo.ln thissomeofscanningelectronmicrograph,the eoithelialcellshavebeenremovedtoexposethe uppersurfaceof the matlikebasallamina.A networkof collagenfibrilsin the underlyingconnectivetissueinteractswith the lower face of theof RobertTrelstad.)lamina.(Courtesy1166Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixperlecantype lV collagen-------------=-=-'----------aFigure19-41The comparativeshapesand sizesof some of the majorextracellularmatrix macromolecules.Proteinis shown in green,andglycosaminoglycanin red.aar nidogenf i b r i l l a cr o l l a g e niio.on"ain{aggrecan1 0 0n mIong polypeptide chains (a, B, and 1) held together by disulfide bonds andarranged in the shape of an asymmetric bouquet, like a bunch of three flowerswhose stems are twisted together at the foot but whose heads remain separate(Figure 19-42).
These heterotrimers can self-assemble in uitro into a network,largely through interactions between their heads, although interaction with cellsis needed to organize the the network into an orderly sheet. Since there are several isoforms of each type of chain, and these can associatein different combinations, many different laminins can be produced, creating basal laminae withdistinctive properties.
The laminin y-1 chain is, however, a component of mostlaminin heterotrimers; mice lacking it die during embryogenesis because theyare unable to make basal lamina.TypelV CollagenGivesthe BasalLaminaTensileStrengthTlrpe IV collagen is a second essentialcomponent of mature basal laminae, andit, too, exists in several isoforms. Like the fibrillar collagensthat constitute thebulk of the protein in connective tissues such as bone or tendon (discussedlater), type IV collagen molecules consist of three separately syrrthesizedlongprotein chains that twist together to form a ropelike superhelix; but they differfrom the fibrillar collagens in that the triple-stranded helical structure is interrupted in more than 20 regions, allowing multiple bends. The tlpe IV collagenmolecules interact via their terminal domains to assemble extracellularly into aflexible, felt-like network.
In this way, type IV collagen gives the basal laminatensile strength.But how do the networks of laminin and type IV collagen bond to oneanother and to the surfacesof the cells that sit on the basal lamina? Why do theyform a two-dimensional sheet, rather than a three-dimensional gel? Themolecules of laminin have severalfunctional domains, including one that bindsto the perlecan proteoglycan, one that binds to the nidogen protein, and tvvo ormore that bind to laminin receptor proteins on the surface of cells.
Type IV collagen also has domains that bind nidogen and perlecan. It is thought, therefore,i ntegrinsdystroglycanpenecan(A)Figure19-42The structureof laminin.(A)Thesubunitsof a laminin-1molecule,and someof their bindingsitesfor othermolecules(yellowboxes).Lamininis amultidomainglycoproteincomposedofthree polypeptides(s, 0, and y) that aredisulfide-bondedinto an asymmetriccrosslikestructure.Eachof the polypeptidechainsis morethan 1500aminoacidslong.Fivetypes of o chains,three types ofB chains,and threetypesof "ychainsareknown;in principle,they canassembletoform 45 (5 x 3 x 3) lamininisoforms.Severalsuch isoformshavebeenfound,eachwith a characteristictissuedistribution.Throughtheir bindingsitesforother proteins,lamininmoleculesplayacentralpart in organizingthe assemblyofbasallaminasand anchoringthem to cells.(B)Electronmicrographsof lamininmoleculesshadowedwith platinum.(8,from J.
Engelet al.,J. Mol.Biol.-1 20,1981.With permission150:97fromAcademicPress.)THEBASALLAMINA1167(A)nidogennncollagenZ\\\Int(=r',\\r'type lV collageni ntegrinc*"!.*--*+('\\that nidogen and perlecan serve as Iinkers to connect the laminin and type IVcollagen networks once the laminin is in place (Figure f 9-43).The laminin molecules that generate the initial sheet structure first join toeach other while bound to receptors on the surface of the cells that producethem. The cell-surfacereceptors are of severalsorts. Many of them are membersof the integrin family; another important type of laminin receptor is dystroglycan, aproleoglycan with a core protein that spans the cell membrane, danglingits glycosaminoglycan polysaccharide chains in the extracellular space.Together,these receptors organize basal lamina assembly:theyhold the lamininmolecules by their feet, leaving the laminin heads positioned to interact so as toform a two-dimensional network.
This laminin network then presumably coordinates the assembly of the other basal lamina components.BasalLaminaeHaveDiverseFunctionsAs we have mentioned, in the kidney glomerulus, an unusually thick basal lamina acts as one of the layers of a molecular filter, helping to prevent the passageof macromolecules from the blood into the urine as urine is formed (seeFigure19-39).The proteoglycan in the basal lamina seemsto be important for this function: when its GAG chains are removed by specific enz)rynes,the filtering properties of the lamina are destroyed. Type IV collagen also has a role: in a humanhereditary kidney disorder (Alport syndrome), mutations in type IV collagengenes result in an irregularly thickened and dysfunctional glomerular filter.Laminin mutations, too, can disrupt the function of the kidney filter, but in a different way-by interfering with the differentiation of the cells that contact it andsupport it.Figure 19-43 A model of the molecularstructureof a basallamina.(A)The basallaminaisformedby specificinteractions(B)betweenthe proteinslaminin,type lVcollagen,and nidogen,and theproteoglycanperlecan.Arows in (B)that can bind directlyconnectmoleculesto eachother.Therearevariousisoformsof type lV collagenand laminin,eachwithtissuedistribution.a distinctivelamininreceptorsTransmembrane(integrinsin the plasmaand dystroglycan)membranearethoughtto organizetheof the basallamina;onlytheassemblyintegrinsareshown.(BasedonH.
Colognatoand P.D.Yurchenco,Dev.Dyn.218:213-234,2000.With permissionfromWiley-Liss.)1 168Chapter19:Cell Junctions,Cell Adhesion,and the ExtracellularMatrixThe basal lamina can act as a selective barrier to the movement of cells, aswell as a filter for molecules. The lamina beneath an epithelium, for example,usually prevents fibroblasts in the underlying connective tissue from makingcontact with the epithelial cells.
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