H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 91
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Cell Biol. 103:393. Part (b), seeL. M. Shaw and B. Olson, 1991, Trends Biochem. Sci. 18:191.]6.4 • The Extracellular Matrix of Nonepithelial Tissuesular domains at both ends. The lateral association of twotype VI monomers generates an “antiparallel” dimer. Theend-to-end association of these dimers through their globular domains forms type VI “microfibrils.” These microfibrils have a beads-on-a-string appearance, with about 60nm-long triple-helical regions separated by 40-nm-long globular domains.The fibrils of type II collagen, the major collagen in cartilage, are smaller in diameter than type I fibrils and are oriented randomly in a viscous proteoglycan matrix.
The rigidcollagen fibrils impart a strength and compressibility to thematrix and allow it to resist large deformations in shape.This property allows joints to absorb shocks. Type II fibrilsare cross-linked to matrix proteoglycans by type IX collagen,another fibril-associated collagen. Type IX collagen and several related types have two or three triple-helical segmentsconnected by flexible kinks and an N-terminal globular segment (Figure 6-22b). The globular N-terminal segment oftype IX collagen extends from the fibrils at the end of oneof its helical segments, as does a GAG chain that is sometimes linked to one of the type IX chains. These protrudingnonhelical structures are thought to anchor the type II fibrilto proteoglycans and other components of the matrix.
Theinterrupted triple-helical structure of type IX and related collagens prevents them from assembling into fibrils, althoughthey can associate with fibrils formed from other collagentypes and form covalent cross-links to them.Certain mutations in the genes encoding collagen1(I) or 2(I) chains, which form type I collagen,lead to osteogenesis imperfecta, or brittle-bone disease. Because every third position in a collagen chain mustbe a glycine for the triple helix to form (see Figure 6-14), mutations of glycine to almost any other amino acid are deleterious, resulting in poorly formed and unstable helices. Onlyone defective chain of the three in a collagen molecule candisrupt the whole molecule’s triple-helical structure and function.
A mutation in a single copy (allele) of either the 1(I)gene or the 2(I) gene, which are located on nonsex chromosomes (autosomes), can cause this disorder. Thus it normally shows autosomal dominant inheritance (Chapter 9). ❚Hyaluronan Resists Compression and FacilitatesCell MigrationHyaluronan, also called hyaluronic acid (HA) or hyaluronate, is a nonsulfated GAG formed as a disaccharide repeat composed of glucuronic acid and N-acetylglucosamine(see Figure 6-17a) by a plasma-membrane-bound enzyme(HA synthase) and is directly secreted into the extracellularspace.
It is a major component of the extracellular matrixthat surrounds migrating and proliferating cells, particularlyin embryonic tissues. In addition, as will be described shortly,hyaluronan forms the backbone of complex proteoglycan aggregates found in many extracellular matrices, particularlycartilage. Because of its remarkable physical properties,hyaluronan imparts stiffness and resilience as well as a lu-219bricating quality to many types of connective tissue such asjoints.Hyaluronan molecules range in length from a few disaccharide repeats to ≈25,000. The typical hyaluronan in jointssuch as the elbow has 10,000 repeats for a total mass of4 106 Da and length of 10 µm (about the diameter of asmall cell). Individual segments of a hyaluronan moleculefold into a rodlike conformation because of the glycosidiclinkages between the sugars and extensive intrachain hydrogen bonding.
Mutual repulsion between negatively chargedcarboxylate groups that protrude outward at regular intervals also contributes to these local rigid structures. Overall,however, hyaluronan is not a long, rigid rod as is fibrillar collagen; rather, in solution it is very flexible, bending and twisting into many conformations, forming a random coil.Because of the large number of anionic residues on itssurface, the typical hyaluronan molecule binds a largeamount of water and behaves as if it were a large hydratedsphere with a diameter of ≈500 nm. As the concentration ofhyaluronan increases, the long chains begin to entangle,forming a viscous gel. Even at low concentrations, hyaluronan forms a hydrated gel; when placed in a confining space,such as in a matrix between two cells, the long hyaluronanmolecules will tend to push outward.
This outward pushingcreates a swelling, or turgor pressure, within the extracellular space. In addition, the binding of cations by COOgroups on the surface of hyaluronan increases the concentration of ions and thus the osmotic pressure in the gel. As aresult, large amounts of water are taken up into the matrix,contributing to the turgor pressure. These swelling forcesgive connective tissues their ability to resist compressionforces, in contrast with collagen fibers, which are able to resist stretching forces.Hyaluronan is bound to the surface of many migratingcells by a number of adhesion receptors (e.g., one calledCD44) containing HA-binding domains, each with a similarthree-dimensional conformation.
Because of its loose, hydrated, porous nature, the hyaluronan “coat” bound to cellsappears to keep cells apart from one another, giving themthe freedom to move about and proliferate. The cessation ofcell movement and the initiation of cell–cell attachments arefrequently correlated with a decrease in hyaluronan, a decrease in HA-binding cell-surface molecules, and an increasein the extracellular enzyme hyaluronidase, which degradeshyaluronan in the matrix. These functions of hyaluronanare particularly important during the many cell migrationsthat facilitate differentiation and in the release of amammalian egg cell (oocyte) from its surrounding cells afterovulation.Association of Hyaluronan and ProteoglycansForms Large, Complex AggregatesThe predominant proteoglycan in cartilage, called aggrecan,assembles with hyaluronan into very large aggregates, illustrative of the complex structures that proteoglycans sometimes form. The backbone of the cartilage proteoglycan220CHAPTER 6 • Integrating Cells into Tissuesaggregate is a long molecule of hyaluronan to which multipleaggrecan molecules are bound tightly but noncovalently (Figure 6-22a).
A single aggrecan aggregate, one of the largestmacromolecular complexes known, can be more than 4 mmlong and have a volume larger than that of a bacterial cell.Hyaluronan molecule(a)Aggrecan(b)300 nmHyaluronan moleculeLink proteinKeratansulfateN-terminalHyaluronan-bindingdomainChondroitinsulfateLinkingsugarsAggrecan core protein▲ FIGURE 6-22 Structure of proteoglycan aggregate fromcartilage. (a) Electron micrograph of an aggrecan aggregate fromfetal bovine epiphyseal cartilage.
Aggrecan core proteins arebound at ≈40-nm intervals to a molecule of hyaluronan.(b) Schematic representation of an aggrecan monomer bound tohyaluronan. In aggrecan, both keratan sulfate and chondroitinsulfate chains are attached to the core protein. The N-terminaldomain of the core protein binds noncovalently to a hyaluronanmolecule. Binding is facilitated by a link protein, which binds toboth the hyaluronan molecule and the aggrecan core protein.Each aggrecan core protein has 127 Ser-Gly sequences at whichGAG chains can be added.
The molecular weight of an aggrecanmonomer averages 2 106. The entire aggregate, which maycontain upward of 100 aggrecan monomers, has a molecularweight in excess of 2 108. [Part (a) from J. A. Buckwalter andL. Rosenberg, 1983, Coll. Rel. Res. 3:489; courtesy of L. Rosenberg.]These aggregates give cartilage its unique gel-like propertiesand its resistance to deformation, essential for distributingthe load in weight-bearing joints.The aggrecan core protein (≈250,000 MW) has one Nterminal globular domain that binds with high affinity to aspecific decasaccharide sequence within hyaluronan.
Thisspecific sequence is generated by covalent modification ofsome of the repeating disaccharides in the hyaluronan chain.The interaction between aggrecan and hyaluronan is facilitated by a link protein that binds to both the aggrecan coreprotein and hyaluronan (Figure 6-22b). Aggrecan and thelink protein have in common a “link” domain, ≈100 aminoacids long, that is found in numerous matrix and cellsurface hyaluronan-binding proteins in both cartilaginousand noncartilaginous tissues. Almost certainly these proteinsarose in the course of evolution from a single ancestral genethat encoded just this domain.The importance of the GAG chains that are part ofvarious matrix proteoglycans is illustrated by therare humans who have a genetic defect in one ofthe enzymes required for synthesis of the GAG dermatan sulfate.
These persons have many defects in their bones, joints,and muscles; do not grow to normal height; and have wrinkled skin, giving them a prematurely aged appearance. ❚Fibronectins Connect Many Cells to FibrousCollagens and Other Matrix ComponentsMany different cell types synthesize fibronectin, an abundantmultiadhesive matrix protein found in all vertebrates. Thediscovery that fibronectin functions as an adhesive moleculestemmed from observations that it is present on the surfacesof normal fibroblastic cells, which adhere tightly to petridishes in laboratory experiments, but is absent from the surfaces of tumorigenic cells, which adhere weakly.
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