Crosslinking elastin formation

For purposes of this manuscript, we wish to concentrate only on the steps leading to the formation of desmosines, amino acids found predominantly in elastin. With respect to their formation, the following suggests their spontaneous formation from peptidyl lysine and the oxidation product, peptidyl allysine. Narayanan et al. (28,29) have shown that when purified lysyl oxidase and non-crosslined elastin, specifically tropoelastin, are incubated together, the desmosines are formed. Desmosine formation, however, only occurs at temperatures that favor fibrillar arrangements of tropoelastin. Subsequently, it is felt that the maturation of non-crosslinked elastin into cross-linked elastin appears to involve only two major steps, namely insolublization through the formation of fibrils and fixation of the fibrils by crosslinking. 

Elastin is a heavily crosslinked biopolymer that is formed in a process named elastogenesis. In this section, the role of elastin and the different steps of elastin production will be described, starting with transcription of the genetic code and processing of the primary transcript, followed by translation into the elastin precursor protein and its transport to the extracellular matrix. Finally, the crosslinking and fiber formation, which result in the transition from tropoelastin to elastin, are described. 

Fig. 4 Structures and formation routes of crosslinks in elastin. In the first step, lysine is catalyti-cally converted to allysine by lysyl oxidase all subsequent condensation steps are spontaneous...

Copper is an essential component of numerous key metalloenzymes which are critical in melanin formation, myelin formation and crosslinking of collagen and elastin. Copper plays a vital role in hemopoiesis, maintenance of vascular and skeletal integrity, and structure and function of the nervous system. Thus a deficiency of copper can lead to a variety of adverse effects such as increased fragility in bones, aneurysm formation in arteries and a loss of lysyl oxidase activity in cartilage.54 57 Articles on copper also appear in Siget1, volumes 3 and 5, all of volumes 12 and 13, and volume 14,... 

In vivo elastin fiber formation requires the coordination of a number of important processes. These include the control of intracellular transcription and translation of tropoelastin, intracellular processing of the protein, secretion of the protein into the extracellular space, delivery of tropoelastin monomers to sites of elastogenesis, alignment of the monomers with previously accreted tropoelastin through associating microfibrillar proteins, and finally, the conversion to the insoluble elastin polymer through the crosslinking action of lysyl oxidase (Fig. 2). 

Elastin is a macromolecule synthesized as a 70,000 single peptide chain, termed tropoelastin and secreted into the extracellular matrix where it is rapidly crosslinked to form mature elastin. The carboxy-terminal end of elastin is highly conserved with the sequence Gly-Gly-Ala-Cys-Leu-Gly-Leu-Ala-Cys-Gly-Arg-Lys-Arg-Lys. The two Cys residues that form disulfide crosslinks are found in this region as well as a positively charged pocket of residues that is believed to be the site of interaction with microfibrillar protein residues. Hydrophobic alanine-rich sequences are known to form a helices in elastin these sequences are found near lysine residues that form crosslinks between two or more chains. Alanine residues not adjacent to lysine residues found near proline and other bulky hydrophobic amino acids inhibit a helix formation. Additional evidence exists for (3 structures and 3 turns within elastin thereby giving an overall model of the molecule that contains helical stiff segments connected by flexible segments. 

This review focuses upon the post-translational modification and chemical changes that occur in elastin. Outlined are the steps currently recognized as important in the assembly of pro-fibrillar elastin subunits into mature fibers. Descriptions of some of the proposed mechanisms that appear important to the process are also presented. It will be emphasized that from the standpoint of protein deterioration, elastin is a very novel protein. Under normal circumstances, the final product of elastin metabolism, the elastin fiber does not undergo degradation that is easily measured. Unlike the metabolism of many other proteins, deterioration or degradation is most evident biochemically in the initial stages of synthesis rather than as a consequence of maturation. Since the presence of crosslinks is an essential component of mature elastin, a section of this review also addresses important features of crosslink formation. 

Dunn, D. M., and Franzblau, C., 1982, Effects of ascorbate on insoluble elastin accumulation and crosslink formation in rabbit pulmonary artery smooth muscle cultures. Biochemistry 18 4195-4202. 

F. Formation of crosslinks in elastin forming desmosine and isodesmosine (Davis and... 

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