Ch 19 Essay Questions

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  1. Explain the diversity of the ECM.
    a. The matrix can become calcified to form the bones or teeth, or transparent to form the cornea, or it can adopt the ropelike organization that gives tendons their enormous tensile strength. It is more than a physical support. It has an active and complex role in regulating the behavior of the cells that touch it, inhabit it, or crawl through its meshes, influencing their survival, development, migration, proliferation, shape, and function
  2. How is the matrix in the connective tissue constructed?
    a. It is constructed from the same two main classes of macromolecules as in basal laminae: glycosaminoglycan polysaccharide chains, usually covalently linked to protein in the form of proteoglycans, and fibrous proteins such as collagen
  3. What are the four main groups of GAGs?
    • hyaluronan
    • chondroitin sulfate and dermatan sulfate
    • heparin sulfate
    • keratan sulfate
  4. What is the structure of GAGs and why?
    a. Because polysaccharide chains are too stiff to fold up into the compact globular structures that polypeptide chains typically form and they are highly hydrophilic, GAGs tend to adopt highly extended conformations that occupy a huge volume relative to their mass, and they form gels even at very low concentrations.
  5. What can GAGs do due to their characteristics?
    a. Because they form porous hydrated gels, GAG chains fill most of the extracellular space. Their high density of negative charges attracts a cloud of cations, especially Na+, that are osmotically active, causing large amounts of water to be sucked into the matrix. This creates a swelling pressure, or turgor, that enables the matrix to withstand compressive forces.
  6. What makes hyaluronans different?
    • it contains no sulfated sugars,
    • all its disaccharide units are identical,
    • its chain length is enormous,
    • it is not generally linked covalently to any core protein.
    • hyaluronan is spun out directly from the cell surface by an enzyme complex embedded in the plasma membrane.
  7. What is hyaluronan's function?
    • role in resisting compressive forces in tissues and joints.
    • important as a space
    • filler during embryonic development, where it can be used to force a change in
    • the shape of the structure, as a small quantity expands with water to occupy a
    • large volume.
    • can deform the epithelium by creating a cell-free space beneath it, into which cells subsequently migrate. When cell migration ends, the excess hyaluronan is essentially degraded by hyaluronidase.
    • produced in large quantities during wound healing, and it is an important constituent of
    • joint fluid, in which it serves as a lubricant.
  8. Explain proteoglycans.
    a.       They are produced by most animal cells. Membrane-bound ribosoems make the polypeptide chain, or core protein, of a proteoglycan, which is then threaded into the lumne of the ER. The polysaccharide chains are mainly assembled on this core protein in the Golgi apparatus before delivery to the exterior of the cell by exocytosis. First, a specil linkage tetrasaccharide is attached to a serine side chain on the core protein to serve as a primer for polysaccharide growth; then, one sugar at a time is added by specific glycosyl transferases. While still in the Golgi apparatus, many of the polymerized sugars are covalently modified by a sequential and coordinated series of reactions. Epimerizations alter the configuration of the substituents around individual carbon atoms in the sugar molecule; sulfations increase the negative charge. 
  9. 1)      Explain the size of proteoglycans using examples.
    • a.       They can be huge.
    •                                                                i.      Aggrecan: 3 x 106 daltons; major component of cartilage
    • b.      They can be small
    •                                                                i.      Decorin, secreted by fibroblasts, has a single GAG chain; binds to collagen fibrils and regulates fibril assembly and fibril diameter
  10. 1)      Explain the funcitons of proteoglycans.
    • a.       GAG chains can form gels of varying pore size and charge density; one possible function is to serve as selective sieves to regulate the traffic of molecules and cells according to their size and charge
    • b.      They have an important role in chemical signaling between cells. They bind various secreted signal molecules, such as certain protein growth factors—controllling their diffusion through the matrix, their range of action, and their lifetime, as well as enhancing or inhibiting their signaling activity.
    • c.       They also bind, and regulate the activities of, other types of secreted proteins, including proteolytic enzymes and protease inhibitors.
  11. 1)      What else can proteogylcans do in reference to their location? 
    a.       Not all are secreted components of the ECM. Some are in the membrane and have their core protein either inserted across the lipid bilayer or attached to the lipid bilayer by a GPI anchor. Some of these plasma membrane proteoglycans act as co-receptors that collaborate with conventional cell-surface receptor proteins. In addition, some conventional receptors have one or more GAG chains and are therefore proteoglycans themselves
  12. What does proline do in collagen?
    a.       Proline stabilizes the helical conformation in each alpha chain while glycine is regularly spaced at every third residue throughout the central region of the alpha chain. Being the smallest amino acid, glycine allows the three helical alpha chains to pack tightly together to form the final collagen superhelix. 
  13. What do individual collagen polypeptide chains undergo?
    • a.       After synthesis on membrane-bound ribosomes, they are injected into the lumen of the ER as pro-alpha hains. These precursors have the short N-terminal signal peptide required to direct the nascent polypeptide to the ER, as well as propeptides at both ends that are clipped off at a later step of collagen assembly.
    • Moreover, in the lumen of the ER, selected prolines and lysines are hydroxylated and some hydroxyl-lysines are glycosylated.
    • Each pro-alpha chain then combines with two others to form a hydrogen-bonded, triple-stranded, helical molecule called procollagen. 
  14. 1)      Explain what happens in hydroxylysines and hydroxyprolines.
    a.       In collagen, the hydroxyl groups are thought to form interchain hydrogen bonds that help stabilize the triple stranded helx. Conditions that prevent hydroxylation have serious consequences. 
  15. After secretion, what occurs?
    a.       The propeptides are removed by specific proteolytic enzymes outside the cell. This converts the procollagen molecules to collagen molecules, which assemble in the extracellular space to form much larger collagen fibrils. 
  16. What is the function of a propeptide?
    • a.       First, they guide the intracellular formation of the triple-stranded collagen molecules
    • b.      Second, because they are retained until after secretion, they prevent the intracellular formation of large collagen fibrils, which could be catastrophic for the cell
  17. What is the process of fibril formation driven by?
    a.       It is driven by the tendency of the collagen molecules to self-assemble. The fibrils begin to form close to the cell surface, often in deep infoldings of the plasma membrane formed by the fusion of secretory vesicles with the cell surface. After the fibrils have formed in the ECS, they are strengthened by the formation of covalent cross-links between lysine residues of the constituent collagen molecules. The types of covalent bonds involved are found only in collagen and elastin. 
  18. What are the steps in the synthesis and assembly of collagen fibrils?
    • a.       Synthesis of pro-alpha chain
    • b.      Hydroxylation of selected prolines and lysines
    • c.       Glycosylation of selected hydroxylysines
    • d.      Self-assembly of three pro-alpha chains
    • e.      Procollagen triple-helix formation
    • f.        Secretion
    • g.       Cleavage of propeptides
    • h.      Self-assembly into fibril
    • i.         Aggregation of collagen fibrils to form a collagen fiber
  19. How do collagen fibrils contrast to GAGs?
    a.       They form structures that resist tensile forces. The fibrils have various diameters and are organized in different ways in different tissues. 
  20. 1)      What do connective tissue cells themselves determine? 
    a.       The size and arrangement of the collagen fibrils are determined. 
  21. 1)      How is it possible for fibrils composed of the same mixture of fibrillary collagen molecuels to have different arrangements in different tissues? 
    a.       This is achieved due to the fact that cells can regulate disposition of the collagen molecules after secretion by guiding collagen fibril formation in close association with the plasma membrane.  In addition, cells can influence this organization by secreting, along with their fibrillary collagens, different kidns and amounts of other matrix macromolecules. In particular, they secrete the fibrous protein fibronectin, and this precedes the formation of collagen fibrils and helps guide their organization
  22. 1)      How do fibril-associated collagens differ from fibrillar collagens.
    • a.       Their triple-stranded helical structure is interrupted by one or two short nonhelical domains, which makes the molecuels more flexible than fibrillary collagen molecules
    • b.      They are not cleaved after secretion and therefore retain their propeptides
    • c.       They do not aggregate with one another to form fibrils in the extracellular space. Instead, they bind in a periodic manner to the surface of fibrils formed by the fibrillary collagens.
    • d.      Fibril-associated colalgens are thought to mediate the interactions of collagen fibrils with one another and with other matrix macromolecules to help determine the organization of the fibrils in the matrix
  23. 1)      Explain interactions of fibroblasts.
    a.       A cluster of fibroblasts surrounds itself with a capsule of densely packed and circumferentilly oriented collagen fibers. The fibroblasts influence the alignment of the collagen fibers, and the collagen fibers in turn affect the distribution of the fibroblasts.
  24. Fibroblats may have a similar role in what?
    a.       Fibroblasts may have a similar role in organizing the extracellular matrix inside the body, first of all synthesizing the collagen fibrils and depositing them in the correct orientation, then working on the matrix they have secreted, crawling over it and tugging on it so as to create tendons and ligaments and the tough, dense layers of connective tissue that ensheathe and bind together most organs.
  25. Explain the elastin protein
    a.       It is composed of two types of short segments that alternate along the polypeptide chain: hydrophobic segments, which are responsible for the elastic properties of the molecule; and alanine-and lysine-rich alpha-helical segments, which form cross-links between adjacent molecules. Each segment is encoded by a separate exon. It seems that parts of the elastin polypeptide chain, like the polymer chains in ordinary ribber, adopt a loose “random coil” conformation, and it is the random coil nature of the component molecules cross-linked into the elastic fiber network that allows the network to stretch and recoil like a rubber band. 
  26. 1)      Aside from elastin, what else do elastic fibers consist of? 
    • a.       The elastin core is covered with a sheath of microfibrils, which has a dimater of about 10 nm. The microfibrils appear before elastin in developing tissues and seems to provide scaffolding to guide elastin deposition. Arrays of microfibrils are elastic in their own right, and in some places they persist in the absence of elastin
    • b.      Microfibrils are composed of a number of distinct glycoproteins, including the large glycoprotein fibrillin, which binds to elastin and is essential for the integrity of elastic fibers. 
  27. What else does the ECM consist of?
    a.       It contains a number of noncollagen proteins that have multiple domains, each with specific bndding sties for other matrix macromolecules and for receptors on the surface of cells. These proteins therefore contribute to both organizing the matrix and helping cells attach to it. Like the proteoglycans, they also guide cell movement in developing tissues, by serving as tracks along which cells can migrate or as repellents that keep cells out of forbidden areas. 
  28. How can fibronectin exist?
    a.       It can exist in a soluble form, circulating in the blood and other body fluids, and as insoluble fibronectin fibrils, in which fibronectin dimers are cross-linked to one another by additional disulfide bonds and form part of the ECM. Unlike fibrillary collagen molecules, which can self-assemble into fibrils, fibronectin molecules assemble into fibrils only on the surface of cells, and only where those cells possess appropriate fibronectin-binding protiens—in particular, integrins. 
  29. What can the integrins provide for the fibronectin and fibronectin-binding proteins?
    The integrins provide a linkage from the fibronectin outside the cell to the actin cytoskeleton inside it. The linkage transmits tension to the fibronectin molecules and stretches them, exposing a cryptic binding site int eh fibronectin molecules. This allows them to bind directly to one another and to recruit additional fibronectin molecules to form a fibril. This dependence on tension and interaction with cell suracces ensures that fibronectin fibrils assemble where there is a mechanical need for them and not in inappropriate locations such as the bloodstream.
  30. Explain treatment of fibronectin
    a.       When fibronectin is treated with a low concentration of a proteolytic enzyme, the polypeptide chain is cut in the connecting regions between the domains, leaving the domains themselves intact. It is shown that its domain binds to collagen, another to heparin, another to specific receptors, etc. 
  31. Explain the RGD sequence
    a.       It isArg-Gly-Asp, or RGD. It is a central feature of the cell-binding site. Short peptides with this sequence can compete with fibronectin for the biding site on cells, tehereby inhibiting the attachment of cells to a fibronectin matrix. If these peptides are coupled to a solid surface, they cause cells to adhere to it
  32. How do other proteins use RGD sequences?
    a.       Several EC proteins have an RGD sequence that mediates cell-surface binding.  The cell-surface receptors that bind RGD-containing proteins are members of the integrin family. Each integrin specifically recognizes its own small set of matrix molecules, indicating htat tight binding requires more than just the RGD sequence. Moreover, RGD sequence are not the only sequence motifs used for binding to integrins: many integrins recognize and bind to other motifs instead. 
  33. What is also important besides making and binding to the ECM?
    a.       The ability of cells to degrade and destroy ECM is important and is required in processes such as tisse repair
  34. 1)      From the point of view of individual cells, why is the ability to cut through matrix crucial? 
    a.       It enables them to divide while embedded in matrix and it enables them to travel through it. Cells in connective tissues generally need to be able to stretch out in order to divide. If a cell lacks the enzyme needed to cut through the surrounding matrix or is embedded in a matrix that resists their action, it remains rounded, unable to extend processes because the matrix is impenetrable. As a result, the cell is strongly inhibited from dividing, as well as being hindered from migrating. 
  35. 1)      More specific than degradation, what is important? 
    a.       Localized degradation of matrix components is important because it is require wherever cells have to escape from confinement by a basal lamina. It is needed during normal branching growth of epithelial structures such as glands to allow the population of epithelial cells to expand and needed also when white blood cells migrate across the basal lamina of a blood vessel into tissues in response to infection or injury. 
  36. 1)      What carries out the degradation? 
    a.       Proteases that act close to the cells that produce them degrade the matrix. Thus, antibodie that recognize the products of proteolytic cleavage stain matrix only around cells. Many of these proteases belong to one of two general classes. Most are matrix metalloproteases, which depend on bound Ca2+ or Zn2+ for activity; the others are serine proteases, which have a highly reactive serine in their active site. 
  37. How do metalloproteases and serine proteases cooperate with one another?
    a.       Together, metalloproteases and serine proteases cooperate to degrade matrix proteins such as collagen, laminin, and fibronectin. Some metalloproteases, such as the collagenases, are highly specific, cleaving particular proteins at a small number o sites. In this way, the structural integrity of the matrix is largely retained, while the limited amount of proteolysis that occurs is sufficient for cell migration. Other metalloprotease may be less specific, but, because they are anchored to the plasma membrane, they can act just where they are needed; it is this type of matrix metalloprotease that is crucial for a cell’s ability to divide when embedded in matrix. 
  38. 1)      What are the basic controls for degradation of matrix components?
    • a.       Local activation: many proteases are secreted as inactive precursors that can be activated locally when needed.
    •                                                                i.      Ex: plasminogen
    • b.      Confinement by cell-surface receptors: many cells have receptors on their surface that bind proteases, thereby confining the enzyme to the sites here it is needed.
    •                                                                i.      Ex: urokinase-type plasminogen activator
    • c.       Secretion of inhibitors: the action of protease is confined to specific areas by various secreted protease inhibitors, including the tissue inhibitors of metalloproteases (TIMPs) and the serine protease inhibitors known as serpins
    •                                                                i.      The inhibitors are protease-specific and bind tightly to the activated enzyme, blocking its activity. 
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Ch 19 Essay Questions
2015-05-06 17:48:17
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