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| Figure 27.5 Desmosine - a multichain crosslink in elastin. Allysine and dehydrolysinonorleucine residues in adjacent elastin chains react to form the three-dimensional elastic polymer, crosslinked by desmosine. |
Epidermolysis bullosa is a rare heritable disorder characterized by severe blistering of the skin and epithelial tissue. Three kinds are known:
- simplex: blistering in the epidermis, caused by defects in keratin filaments;
- junctional: blistering in the dermal-epidermal junction, caused by defects in laminin;
- dystrophic: blistering in the dermis, caused by mutations in the gene encoding type VII collagen.
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| Epidermolysis bullosa illustrates the multifactorial nature of connective tissue diseases that have similar clinical features. |
Lathyrism is a diet-induced disease characterized by deformation of the spine, dislocation of joints, demineralization of bones, aortic aneurysms, and joint hemorrhages. These problems develop as a result of inhibition of lysyl oxidase, an enzyme required for the crosslinking of collagen chains. Lathyrism can be caused by chronic ingestion of the sweet pea, Lathyrus odoratus, the seeds of which contain β-aminopropionitrile, an irreversible inhibitor of lysyl oxidase. Penicillamine , a sulfhydryl agent used for chelation therapy in heavy-metal toxicity, also causes lathyrism, because of either chelation of copper required for lysyl oxidase activity or reaction with aldehyde groups of (hydroxy)allysine, inhibiting collagen crosslinking reactions. |
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| Fibronectin is a glycoprotein present in the ECM and also in plasma as a soluble protein. It is involved in a large number of biological activities, including cell adhesion, cell migration, cell morphology, embryonic differentiation, and cytoskeletal organization. It has a central role in binding together the many structures of the ECM, including collagens, proteoglycans, and the cell surface. Fibronectin is a dimer of two identical subunits, each of 230 kDa, joined by a pair of disulfide bonds at their C-terminals. Each subunit is organized into domains, known as type I, II, and III domains,
and each of these has several homologous repeating units or modules in its primary structure (Fig. 27.6): there are 12 type I repeats, 2 type II repeats, and 15-17 type III repeats. Each module is independently folded, forming a 'string of beads' type of structure. At least 20 different tissue-specific isoforms of fibronectin have been identified, all produced by alternative splicing of a single precursor messenger ribonucleic acid (mRNA). The alternative splicing is regulated, not only in a tissue-specific manner, but also during embryogenesis, wound healing, and oncogenesis. Plasma fibronectin, secreted mainly by liver cells, lacks two of the type III repeats that are found in cell- and matrix-associated forms of fibronectin.
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| Functional domains in fibronectin have been identified by their binding affinity for other ECM components, including collagen, heparin, fibrin, and the cell surface. The type I modules interact with fibrin, heparin, and collagen, type II modules have collagen-binding domains, and type III modules are involved in binding to heparin and the cell surface. The specific interactions have been further mapped to short stretches of amino acids. A short peptide containing Arg-Gly-Asp (RGD), present in the tenth type III repeat of fibronectin, binds to the integrin family of proteins present on cell surfaces; this sequence is not unique to fibronectin, but is also found in other proteins in the ECM. Another sequence, Pro-X-Ser-Arg-Asn (PXSRN), present in the ninth type III repeat, is implicated in integrin-mediated cell attachment. The integrins are a family of transmembrane proteins that bind extracellular proteins on the outside and cytoskeletal proteins, such as actin, on the inside of the cell, providing a mechanism for communication between the intracellular and extracellular environments of the cell. The loss of fibronectin from the surface of many tumor cells may contribute to their release into the circulation and penetration through the ECM, one of the first steps in tumor metastasis.
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