Lodish H. - Molecular Cell Biology (5ed, Freeman, 2003) (794361), страница 91
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In the fed state, the syndecan extracellular domaindecorated with heparan sulfate chains is released from the surface by proteolysis, thus suppressing the activity of the antisatiety peptides and feeding behavior. In mice engineered tooverexpress the syndecan-1 gene in the hypothalamic region ofthe brain and other tissues, normal control of feeding by antisatiety peptides is disrupted and the animals overeat and become obese. Other examples of proteoglycans interacting withexternal signaling molecules are described in Chapter 14.6.3 • The Extracellular Matrix of Epithelial SheetsOSO3HOHOORHNR = Ac or SO3OSO3OOCOHOOOOOHO3SOOOCO3SHNOOHOSO3OO3SOOHOOO3SHNOH215 FIGURE 6-19 PentasaccharideGAG sequence that regulates theactivity of antithrombin III (ATIII).Sets of modified five-residuesequences in heparin with thecomposition shown here bind to ATIIIand activate it, thereby inhibiting bloodclotting.
The sulfate groups in red typeare essential for this heparin function;the modifications in blue type may bepresent but are not essential. Othersets of modified GAG sequences arethought to regulate the activity ofother target proteins. [Courtesy of RobertRosenberg and Balagurunathan Kuberan.]Modifications in Glycosaminoglycan (GAG)Chains Can Determine Proteoglycan FunctionsAs is the case with the sequence of amino acids in proteins,the arrangement of the sugar residues in GAG chains and themodification of specific sugars (e.g., addition of sulfate) inthe chains can determine their function and that of the proteoglycans containing them.
For example, groupings of certain modified sugars in the GAG chains of heparin sulfateproteoglycans can control the binding of growth factorsto certain receptors, the activities of proteins in the bloodclotting cascade, and the activity of lipoprotein lipase, amembrane-associated enzyme that hydrolyzes triglycerides tofatty acids (Chapter 18).For years, the chemical and structural complexity ofproteoglycans posed a daunting barrier to an analysis oftheir structures and an understanding of their many diversefunctions. In recent years, investigators employing classical and new state-of-the-art biochemical techniques (e.g.,capillary high-pressure liquid chromatography), mass spectrometry, and genetics have begun to elucidate the detailedstructures and functions of these ubiquitous ECM molecules. The results of ongoing studies suggest that sets ofsugar-residue sequences containing some modifications incommon, rather than single unique sequences, are responsible for specifying distinct GAG functions.
A case in pointis a set of five-residue (pentasaccharide) sequences found ina subset of heparin GAGs that control the activity ofantithrombin III (ATIII), an inhibitor of the key bloodclotting protease thrombin. When these pentasaccharide sequences in heparin are sulfated at two specific positions,heparin can activate ATIII, thereby inhibiting clot formation (Figure 6-19). Several other sulfates can be present inthe active pentasaccharide in various combinations, butthey are not essential for the anticlotting activity of heparin. The rationale for generating sets of similar activesequences rather than a single unique sequence and themechanisms that control GAG biosynthetic pathways, permitting the generation of such active sequences, are notwell understood.KEY CONCEPTS OF SECTION 6.3The Extracellular Matrix of Epithelial SheetsThe basal lamina, a thin meshwork of extracellular matrix (ECM) molecules, separates most epithelia and otherorganized groups of cells from adjacent connective tissue.Together, the basal lamina and collagenous reticular lamina form a structure called the basement membrane.■Four ECM proteins are found in all basal laminae (see Figure 6-13): type IV collagen, laminin (a multiadhesive matrixprotein), entactin (nidogen), and perlecan (a proteoglycan).■■ Cell-surface adhesion receptors (e.g., 64 integrin inhemidesmosomes) anchor cells to the basal lamina, which inturn is connected to other ECM components (see Figure 6-1).Repeating sequences of Gly-X-Y give rise to the collagen triple-helical structure (see Figure 6-14).
Different collagens are distinguished by the length and chemical modifications of their chains and by the segments thatinterrupt or flank their triple-helical regions.■The large, flexible molecules of type IV collagen interact end to end and laterally to form a meshlike scaffold towhich other ECM components and adhesion receptors canbind (see Figure 6-15).■Laminin and other multiadhesive matrix proteins aremultidomain molecules that bind multiple adhesion receptors and ECM components.■Proteoglycans consist of membrane-associated or secreted core proteins covalently linked to one or more glycosaminoglycan (GAG) chains, which are linear polymersof sulfated disaccharides.■Perlecan, a large secreted proteoglycan present primarilyin the basal lamina, binds many ECM components and adhesion receptors.■Cell-surface proteoglycans such as the syndecans facilitate cell–matrix interactions and help present certain external signaling molecules to their cell-surface receptors.■216CHAPTER 6 • Integrating Cells into Tissues6.4 The Extracellular Matrixof Nonepithelial TissuesWe have seen how diverse CAMs and adhesion receptorsparticipate in the assembly of animal cells into epithelialsheets that rest on and adhere to a well-defined ECM structure, the basal lamina.
The same or similar molecules mediate and control cell–cell and cell–matrix interactions inconnective, muscle, and neural tissues and between bloodcells and the surrounding vessels. In this section, we consider some of the ECM molecules characteristic of thesenonepithelial tissues. We also describe the synthesis of fibrillar collagens, which are the most abundant proteins inanimals. The interactions entailing CAMs and adhesionreceptors expressed by various nonepithelial cells, whichserve a wide variety of distinctive functions, are covered inSection 6.5.TABLE 6-1 Selected CollagensMoleculeCompositionStructural FeaturesRepresentative TissuesI[1(I)]2[2(I)]300-nm-long fibrilsSkin, tendon, bone, ligaments, dentin, interstitialtissuesII[1(II)]3300-nm-long fibrilsCartilage, vitreous humorIII[1(III)]3300-nm-long fibrils; often with type ISkin, muscle, bloodvesselsV[1(V)2 2(V)],[1(V)3]390-nm-long fibrils with globularN-terminal extension; often with type ICornea, teeth, bone,placenta, skin, smoothmuscleTypeFIBRILLAR COLLAGENSFIBRIL-ASSOCIATED COLLAGENSVI[1(VI)][2(VI)]Lateral association with type I; periodicglobular domainsMost interstitial tissuesIX[1(IX)][2(IX)][3(IX)]Lateral association with type II;N-terminal globular domain; bound GAGCartilage, vitreous humorSHEET-FORMING AND ANCHORING COLLAGENSIV[1(IV)]2[2(IV)]Two-dimensional networkAll basal laminaeVII[1(VII)]3Long fibrilsBelow basal lamina ofthe skinXV[1(XV)]3Core protein of chondroitin sulfateproteoglycanWidespread; near basallamina in muscleTRANSMEMBRANE COLLAGENSXIII[1(XIII)]3Integral membrane proteinHemidesmosomes in skinXVII[1(XVII)]3Integral membrane proteinHemidesmosomes in skinCollectinsOligomers of triple helix; lectin domainsBlood, alveolar spaceC1qOligomers of triple helixBlood (complement)Class A scavengerreceptorsHomotrimeric membrane proteinsMacrophagesHOST DEFENSE COLLAGENSSOURCES:K.
Kuhn, 1987, in R. Mayne and R. Burgeson, eds., Structure and Function of Collagen Types,Academic Press, p. 2; and M. van der Rest and R. Garrone, 1991, FASEB J. 5:2814.6.4 • The Extracellular Matrix of Nonepithelial TissuesFibrillar Collagens Are the Major Fibrous Proteinsin the Extracellular Matrix of Connective TissuesConnective tissue, such as tendon and cartilage, differs fromother solid tissues in that most of its volume is made up ofextracellular matrix rather than cells. This matrix is packedwith insoluble protein fibers and contains proteoglycans,various multiadhesive proteins, and hyaluronan, a very large,nonsulfated GAG. The most abundant fibrous protein inconnective tissue is collagen. Rubberlike elastin fibers, whichcan be stretched and relaxed, also are present in deformablesites (e.g., skin, tendons, heart).
As discussed later, thefibronectins, a family of multiadhesive matrix proteins, formtheir own distinct fibrils in the matrix of some connective tissues. Although several types of cells are found in connectivetissues, the various ECM components are produced largelyby cells called fibroblasts.About 80–90 percent of the collagen in the body consistsof types I, II, and III collagens, located primarily in connective tissues. Because of its abundance in tendon-rich tissuesuch as rat tail, type I collagen is easy to isolate and was thefirst collagen to be characterized. Its fundamental structuralunit is a long (300-nm), thin (1.5-nm-diameter) triple helixconsisting of two 1(I) chains and one 2(I) chain, each precisely 1050 amino acids in length (see Figure 6-14). Thetriple-stranded molecules associate into higher-order poly-mers called collagen fibrils, which in turn often aggregateinto larger bundles called collagen fibers.The minor classes of collagen include fibril-associated collagens, which link the fibrillar collagens to one another or toother ECM components; sheet-forming and anchoring collagens, which form two-dimensional networks in basal laminae(type IV) and connect the basal lamina in skin to the underlying connective tissue (type VII); transmembrane collagens,which function as adhesion receptors; and host defensecollagens, which help the body recognize and eliminatepathogens.
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