Lodish H. - Molecular Cell Biology (5ed, Freeman, 2003) (794361), страница 92
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Table 6-1 lists specific examples in the variousclasses of collagens. Interestingly, several collagens (e.g., typesXVIII and XV) function as core proteins in proteoglycans.Formation of Collagen Fibrils Beginsin the Endoplasmic Reticulumand Is Completed Outside the CellCollagen biosynthesis and secretion follow the normal pathwayfor a secreted protein, which is described in detail in Chapters16 and 17. The collagen chains are synthesized as longerprecursors, called pro- chains, by ribosomes attached to theendoplasmic reticulum (ER). The pro- chains undergo a seriesof covalent modifications and fold into triple-helical procollagen molecules before their release from cells (Figure 6-20).
FIGURE 6-20 Major events in biosynthesis1Rough ERNOHN OHNOHOα1OHS−Sα1α2OOH2OHNNPropeptideNHsp473Procollagen5 Lateral association4GolgicomplexCytosol67 PropeptideExtracellular spacecleavageCollagen molecule8 Fibril assembly and crosslinkingCollagen fibril250nmCross-striations(67 nm)21767 nmof fibrillar collagens. Step 1 : Procollagen chains are synthesized on ribosomes associatedwith the endoplasmic reticulum (ER) membrane,and asparagine-linked oligosaccharides are addedto the C-terminal propeptide.
Step 2 : Propeptidesassociate to form trimers and are covalently linkedby disulfide bonds, and selected residues in theGly- X - Y triplet repeats are covalently modified[certain prolines and lysines are hydroxylated,galactose (Gal) or galactose-glucose (hexagons) isattached to some hydroxylysines, prolines are cis→ trans isomerized]. Step 3 : The modificationsfacilitate zipperlike formation, stabilization of triplehelices, and binding by the chaperone proteinHsp47 (Chapter 16), which may stabilize thehelices or prevent premature aggregation of thetrimers or both. Steps 4 and 5 : The foldedprocollagens are transported to and through theGolgi apparatus, where some lateral associationinto small bundles takes place. The chains arethen secreted (step 6 ),the N- and C- terminalpropeptides are removed (step 7 ), and thetrimers assemble into fibrils and are covalentlycross-linked (step 8 ).
The 67-nm staggering ofthe trimers gives the fibrils a striated appearancein electron micrographs (inset). [Adapted fromA. V. Persikov and B. Brodsky, 2002, Proc. Nat’l.Acad. Sci. USA 99(3):1101–1103.]218CHAPTER 6 • Integrating Cells into TissuesAfter the secretion of procollagen from the cell, extracellular peptidases (e.g., bone morphogenetic protein-1) removethe N-terminal and C-terminal propeptides.
In regard to fibrillar collagens, the resulting molecules, which consist almostentirely of a triple-stranded helix, associate laterally to generate fibrils with a diameter of 50–200 nm. In fibrils, adjacent collagen molecules are displaced from one another by67 nm, about one-quarter of their length. This staggeredarray produces a striated effect that can be seen in electronmicrographs of collagen fibrils (see Figure 6-20, inset). Theunique properties of the fibrous collagens (e.g., types I, II, III)are mainly due to the formation of fibrils.Short non-triple-helical segments at either end of the collagen chains are of particular importance in the formation ofcollagen fibrils.
Lysine and hydroxylysine side chains in thesesegments are covalently modified by extracellular lysyl oxidasesto form aldehydes in place of the amine group at the end of theside chain. These reactive aldehyde groups form covalent crosslinks with lysine, hydroxylysine, and histidine residues in adjacent molecules. These cross-links stabilize the side-by-sidepacking of collagen molecules and generate a strong fibril. Theremoval of the propeptides and covalent cross-linking takeplace in the extracellular space to prevent the potentially catastrophic assembly of fibrils within the cell.I collagen fibers have great tensile strength, tendons can bestretched without being broken. Indeed, gram for gram, typeI collagen is stronger than steel.
Two quantitatively minorfibrillar collagens, type V and type XI, coassemble into fiberswith type I collagen, thereby regulating the structures andproperties of the fibers. Incorporation of type V collagen, forexample, results in smaller-diameter fibers.Type I collagen fibrils are also used as the reinforcingrods in the construction of bone. Bones and teeth are hardand strong because they contain large amounts of dahllite, acrystalline calcium- and phosphate-containing mineral. Mostbones are about 70 percent mineral and 30 percent protein,the vast majority of which is type I collagen.
Bones formwhen certain cells (chondrocytes and osteoblasts) secrete collagen fibrils that are then mineralized by deposition of smalldahllite crystals.In many connective tissues, type VI collagen and proteoglycans are noncovalently bound to the sides of type I fibrilsand may bind the fibrils together to form thicker collagenfibers (Figure 6-21a). Type VI collagen is unusual in that themolecule consists of a relatively short triple helix with glob-(b)(a)The post-translational modifications of pro-chains are crucial for the formation of mature collagen molecules and their assembly into fibrils. Defects in these modifications have serious consequences, asancient mariners frequently experienced.
For example, ascorbic acid (vitamin C) is an essential cofactor for the hydroxylases responsible for adding hydroxyl groups to proline andlysine residues in pro- chains. In cells deprived of ascorbate,as in the disease scurvy, the pro- chains are not hydroxylated sufficiently to form stable triple-helical procollagen atnormal body temperature, and the procollagen that formscannot assemble into normal fibrils.
Without the structuralsupport of collagen, blood vessels, tendons, and skin becomefragile. Because fresh fruit in the diet can supply sufficient vitamin C to support the formation of normal collagen, earlyBritish sailors were provided with limes to prevent scurvy,leading to their being called “limeys.”Rare mutations in lysyl hydroxylase genes cause Brucksyndrome and one form of Ehlers-Danlos syndrome. Bothdisorders are marked by connective-tissue defects, althoughtheir clinical symptoms differ.
❚Type I and II Collagens Form DiverseStructures and Associate with DifferentNonfibrillar CollagensCollagens differ in their ability to form fibers and to organize the fibers into networks. In tendons, for instance, longtype I collagen fibrils are packed side by side in parallel bundles, forming thick collagen fibers. Tendons connect musclesto bones and must withstand enormous forces. Because typeType-I collagen fibrilsType-II collagen fibrilChondroitinsulfateKinkType-VIcollagenType-IXcollagenProteoglycan▲ FIGURE 6-21 Interactions of fibrous collagens withnonfibrous fibril-associated collagens.
(a) In tendons, type Ifibrils are all oriented in the direction of the stress applied to thetendon. Proteoglycans and type VI collagen bind noncovalently tofibrils, coating the surface. The microfibrils of type VI collagen,which contain globular and triple-helical segments, bind to type Ifibrils and link them together into thicker fibers.
(b) In cartilage,type IX collagen molecules are covalently bound at regularintervals along type II fibrils. A chondroitin sulfate chain,covalently linked to the 2(IX) chain at the flexible kink, projectsoutward from the fibril, as does the globular N-terminal region.[Part (a), see R. R. Bruns et al., 1986, J. 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.
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