| Lysyl oxidases: Cloning and characterization of the fourth and the fifth human lysyl oxidase isoenzymes, and the consequences of a targeted inactivation of the first described lysyl oxidase isoenzyme in mice | ||
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Collagens form a multigene family with at least 39 members, the genes for which are known to be dispersed throughout at least 15 chromosomes. Collagens are structural proteins of the extracellular matrix, and are the most abundant proteins in the mammalian body. Collagen molecules consist of three identical or dissimilar polypeptide chains, called α chains, and contain at least one triple-helical collagenous domain with repeating (Gly-X-Y)n sequences, i.e. a glycine residue as every third amino acid, with the frequent presence of proline and 4-hydroxyproline in the X and Y positions, respectively. In addition to the actual collagenous domains, all collagens also contain noncollagenous domains. Most collagen molecules form supramolecular assemblies, and the superfamily can be divided into nine different families based on their polymeric structures or other features: collagens that forms fibrils (types I-III, V and XI); collagens that are located on the surface of fibrils and are called fibril-associated collagens with interupted triple helices (FACIT and structurally related collagens, types IX, XII, XIV, XVI, XIX, XX and XXI); collagens that form hexagonal networks (types VIII and X); the family of type IV collagens found in basement membranes; type VI collagen that forms beaded filaments; type VII collagen that forms anchoring fibrils for basement membranes; collagens with transmembrane domains (types XIII and XVII); and the family of type XV and XVIII collagens. For references and more thorough reviews, see Byers (2001) and Myllyharju & Kivirikko (2001). For detailed information about recently found type XX and XXI collagens, see Koch et al. (2001) and Fitzgerald & Bateman (2001), respectively.
The biosynthesis of the precursors of fibrillar collagens, called procollagens, involves a number of posttranslational modifications. The intracellular modifications require five specific enzymes: three collagen hydroxylases (Kivirikko & Pihlajaniemi 1998, Kivirikko & Myllyharju 1998) and two collagen glycosyltransferases (Kivirikko & Myllylä 1979, Kivirikko 1993, Prockop & Kivirikko 1995). Once outside the cells, the procollagen molecules undergo proteolytic conversion to collagen molecules. The collagen molecules form fibrils and interact with noncollagenous and collagenous proteins, and the fibrils are stabilized by the formation of intra- and intermolecular cross-links. These extracellular modifications of collagens require two specific proteinases to cleave the N- and C-terminal propeptides (Prockop et al. 1998) and specific oxidases to convert certain lysine and hydroxylysine residues to their reactive aldehydes. These oxidases will be discussed in detail in the next sections.
Elastin is the most important component of the elastic fibers found in the extracellular matrix and provides elasticity and resilience to tissues requiring the ability to deform repetitively and reversibly. Ultrastructurally, elastin fibers consist of two major elements: an amorphous component made up of elastin and fibrillar components called microfibrils, which serve as a scaffold for the incorporation of elastin into the amorphous component (Cleary & Gibson 1996). Elastin is an extremely insoluble protein due to extensive cross-linking at lysine residues, and it is amongst the most hydrophobic proteins known. In higher vertebrates, including humans, over 30% of amino acid residues in elastin are glycine residues, and approximately 75 % of the entire sequence is made up of just four hydrophobic amino acids - glycine, valine, alanine, and proline. Tissues rich in elastin include the aorta and large blood vessels (28-32% of the dry mass), lungs (3-7%), elastic ligaments (50%), tendons (4%), and skin (2%) (Vrhovski & Weiss 1998, Debelle & Tamburro 1999).
Tropoelastin, the precursor of elastin, is encoded by a single gene located on chromosome 7q11 in humans and has at least 11 variants due to alternative splicing of the transcripts (Vrhovski & Weiss 1998). Tropoelastin undergoes only minor post-translational modifications, and there is no evidence of glycosylation. Hydroxylation of proline residues occurs to a variable extent, 0-20%, but this hydroxylation is not necessary for the synthesis of the elastic fibre (Vrhovski & Weiss 1998). After translation of tropoelastin, a 67 kDa elastin-binding protein becomes bound to tropoelastin, acting as a chaperone and preventing premature intracellular aggregation of tropoelastin molecules. This association lasts until the complex has been secreted into the extracellular space, where the elastin-binding protein interacts with galactosugars of the microfibrils. At this point the affinity of the elastin-binding protein for elastin decreases dramatically, leading to the release of the tropoelastin molecule into the microfibrilar scaffold (Hinek & Rabinovitch 1994). Before tropoelastin is assembled into the amorphous component of the elastic fiber, it becomes covalently cross-linked by lysyl oxidase, which has been found to be associated with microfibrils (Kagan et al. 1986, Cleary & Gibson 1996). For references and more thorough reviews of elastin and the elastic fiber, see Rosenbloom (1993), Cleary & Gibson (1996), Vrhovski & Weiss (1998) and Debelle & Tamburro (1999).