H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 88
Текст из файла (страница 88)
Thenonhelical regions introduce flexibility into the molecule.Through both lateral associations and interactions entailingthe globular N- and C-termini, type IV collagen moleculesassemble into a branching, irregular two-dimensional fibrousnetwork that forms the lattice on which the basal lamina isbuilt (Figure 6-15).In the kidney, a double basal lamina, the glomerular basement membrane, separates the epitheliumthat lines the urinary space from the endotheliumthat lines the surrounding blood-filled capillaries.
Defects inthis structure, which is responsible for ultrafiltration of theblood and initial urine formation, can lead to renal failure.For instance, mutations that alter the C-terminal globulardomain of certain IV chains are associated with progressive renal failure as well as sensorineural hearing loss andocular abnormalities, a condition known as Alport’ssyndrome. In Goodpasture’s syndrome, a relatively rareautoimmune disease, self-attacking, or “auto,” antibodiesbind to the 3 chains of type IV collagen found in theglomerular basement membrane and lungs.
This bindingsets off an immune response that causes cellular damageresulting in progressive renal failure and pulmonaryhemorrhage.❚DimerTetramer(b) Type IV networkLaminin, a Multiadhesive Matrix Protein, HelpsCross-link Components of the Basal Lamina250 nm▲ FIGURE 6-15 Structure and assembly of type IV collagen.(a) Schematic representation of type IV collagen. This 400-nmlong molecule has a small noncollagenous globular domain at theN-terminus and a large globular domain at the C-terminus. Thetriple helix is interrupted by nonhelical segments that introduceflexible kinks in the molecule. Lateral interactions between triplehelical segments, as well as head-to-head and tail-to-tailinteractions between the globular domains, form dimers,tetramers, and higher-order complexes, yielding a sheetlikenetwork. (b) Electron micrograph of type IV collagen networkformed in vitro.
The lacy appearance results from the flexibility ofthe molecule, the side-to-side binding between triple-helicalsegments (thin arrows), and the interactions between C-terminalglobular domains (thick arrows). [Part (a) adapted from A. Boutaud,2000, J. Biol. Chem. 275:30716. Part (b) courtesy of P. Yurchenco; seeP. Yurchenco and G. C. Ruben, 1987, J. Cell Biol. 105:2559.]Multiadhesive matrix proteins are long, flexible moleculesthat contain multiple domains responsible for binding various types of collagen, other matrix proteins, polysaccharides,cell-surface adhesion receptors, and extracellular signalingmolecules (e.g., growth factors and hormones).
These proteins are important for organizing the other components ofthe extracellular matrix and for regulating cell–matrix adhesion, cell migration, and cell shape in both epithelial andnonepithelial tissues.Laminin, the principal multiadhesive matrix protein inbasal laminae, is a heterotrimeric, cross-shaped protein witha total molecular weight of 820,000 (Figure 6-16). Manylaminin isoforms, containing slightly different polypeptidechains, have been identified. Globular LG domains at the Cterminus of the laminin subunit mediate Ca2-dependentbinding to specific carbohydrates on certain cell-surfacemolecules such as syndecan and dystroglycan.
LG domainsare found in a wide variety of proteins and can mediatebinding to steroids and proteins as well as carbohydrates.For example, LG domains in the chain of laminin can mediate binding to certain integrins, including 64 integrinon epithelial cells.6.3 • The Extracellular Matrix of Epithelial Sheetsα Chain (400,000 MW)(a)(a) Hyaluronan (n <∼ 25,000)β Chain(215,000 MW)Binds type IVcollagenCH2OHO5β(1→3)OOOBinds sulfatedlipids6COO−γ Chain(205,000 MW)OHBinds collagen,sulfated lipids4HOOHα-Helical coiled coil25 nmLG domains,bindcarbohydratesand integrins13On2(b) Chondroitin (or dermatan) sulfate (n <∼ 250)(SO3−)COO−CH2OH(SO3−)OOHOOOOHβ(1→4)Onα/β(1→3)OHD-Glucuronic acid(or L-iduronic acid)(b)NHCOCH3N -AcetylD-galactosamine(c) Heparin/Heparan sulfate (n = 200)COO−OO50 nmβ(1→4)NHCOCH3N -AcetylD-glucosamineD-Glucuronic acidBinds neurites213matrix protein found in all basal laminae.
(a) Schematic modelshowing the general shape, location of globular domains, andcoiled-coil region in which laminin’s three chains are covalentlylinked by several disulfide bonds. Different regions of lamininbind to cell-surface receptors and various matrix components.(b) Electron micrographs of intact laminin molecule, showing itscharacteristic cross appearance (left) and the carbohydratebinding LG domains near the C-terminus (right). [Part (a) adaptedfrom G. R. Martin and R. Timpl, 1987, Ann.
Rev. Cell Biol. 3:57, andK. Yamada, 1991, J. Biol. Chem. 266:12809. Part (b) from R. Timpl et al.,2000, Matrix Biol. 19:309; photograph at right courtesy of Jürgen Engel.]Secreted and Cell-Surface ProteoglycansAre Expressed by Many Cell TypesProteoglycans are a subset of glycoproteins containing covalently linked specialized polysaccharide chains calledglycosaminoglycans (GAGs), which are long linear polymersof specific repeating disaccharides.
Usually one sugar is either a uronic acid (D-glucuronic acid or L-iduronic acid) orD-galactose; the other sugar is N-acetylglucosamine orN-acetylgalactosamine (Figure 6-17). One or both of the sugars contain at least one anionic group (carboxylate or sulfate). Thus each GAG chain bears many negative charges.OOH10 nm▲ FIGURE 6-16 Laminin, a heterotrimeric multiadhesiveα/β(1→4)OH(SO3−)D-Glucuronic orL-iduronic acid(d) Keratan sulfate (n = 20–40)(SO3−)CH2OHβ(1→4)OHOO(SO3−)CH2OHOOHα(1→4)OnNHSO3−(COCH3)N -Acetyl- or N -sulfoD-glucosamine(SO3−)CH2OHOOHβ(1→3)OnOOHD-GalactoseNHCOCH3N -AcetylD-glucosamine▲ FIGURE 6-17 The repeating disaccharides ofglycosaminoglycans (GAGs), the polysaccharide componentsof proteoglycans.
Each of the four classes of GAGs is formed bypolymerization of monomer units into repeats of a particulardisaccharide and subsequent modifications, including addition ofsulfate groups and inversion (epimerization) of the carboxyl groupon carbon 5 of D-glucuronic acid to yield L-iduronic acid. Heparinis generated by hypersulfation of heparan sulfate, whereashyaluronan is unsulfated. The number (n) of disaccharidestypically found in each glycosaminoglycan chain is given. Thesquiggly lines represent covalent bonds that are oriented eitherabove (D-glucuronic acid) or below (L-iduronic acid) the ring.214CHAPTER 6 • Integrating Cells into TissuesGAGs are classified into several major types based on the nature of the repeating disaccharide unit: heparan sulfate,chondroitin sulfate, dermatan sulfate, keratan sulfate, andhyaluronan.
A hypersulfated form of heparan sulfate calledheparin, produced mostly by mast cells, plays a key role inallergic reactions. It is also used medically as an anticlottingdrug because of its ability to activate a natural clotting inhibitor called antithrombin III.As we will see in later chapters, complex signaling pathways direct the emergence of various cell types in the properposition and at the proper time in normal embryonic development. Laboratory generation and analysis of mutants with defects in proteoglycan production in Drosophila melanogaster(fruit fly), C. elegans (roundworm), and mice have clearlyshown that proteoglycans play critical roles in development,most likely as modulators of various signaling pathways.Biosynthesis of Proteoglycans With the exception ofhyaluronan, which is discussed in the next section, all themajor GAGs occur naturally as components of proteoglycans.
Like other secreted and transmembrane glycoproteins,proteoglycan core proteins are synthesized on the endoplasmic reticulum (Chapter 16). The GAG chains are assembledon these cores in the Golgi complex. To generate heparan orchondroitin sulfate chains, a three-sugar “linker” is first attached to the hydroxyl side chains of certain serine residuesin a core protein (Figure 6-18). In contrast, the linkers for theaddition of keratan sulfate chains are oligosaccharide chainsattached to asparagine residues; such N-linked oligosaccharides are present in most glycoproteins, although only a subset carry GAG chains.
All GAG chains are elongated by thealternating addition of sugar monomers to form the disaccharide repeats characteristic of a particular GAG; the chainsare often modified subsequently by the covalent linkage ofsmall molecules such as sulfate. The mechanisms responsible for determining which proteins are modified with GAGs,the sequence of disaccharides to be added, the sites to be sulCoreproteinSO4(GlcUAGalNAc)nGlcUAGalChondroitin sulfaterepeatsGal = galactoseGalNAc = N -acetylgalactosamineGalXylSerLinking sugarsGlcUA = glucuronic acidXyl = xylose▲ FIGURE 6-18 Biosynthesis of heparan and chondroitinsulfate chains in proteoglycans.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
