Translocation and Secretion of Procollagen

After the procollagen polypeptides are assembled into a triple helix, they are secreted by the classical route. They pass through the smooth endoplasmic reticulum and the Golgi complex, where they are packaged into membranous vesicles and secreted into the extracellular space by exo-cytosis. This process requires ATP and may involve microtubules and microfilaments. The conformation of procollagen markedly affects the rate of secretion. Prevention of the formation of a triple helix (e.g., lack of 4-hydroxylation due to vitamin C deficiency) leads to the accumulation of nonhelical propolypeptides within the cistemae of the rough endoplasmic reticulum and a delayed rate in its secretion. 

Conversion of procollagen to collagen requires at least two proteases a procollagen aminoprotease and a procollagen carboxyprotease. The former catalyzes removal of the N-terminal propeptide and the latter removal of the C-terminal propeptide. The two enzymes are endopepti-dases, function at neutral pH, require a bivalent cation such as Ca +, and show a preference for the helical conformation. There appears to be no preferential order for the cleavage of the propeptides. 

The conversion of procollagen to collagen by removal of propeptides seems to be essential for the formation of collagen fibrils. This supposition is supported by studies of two heritable diseases, one found in humans and the other in cattle, sheep, and cats. In both, the defect lies in the removal of N-terminal propeptides and results in impaired fibril formation. The human disorder is the type VII variant of Ehlers-Danlos syndrome (Table 25-5). Affected individuals exhibit marked joint hypermobility, dislocation of joints, short stature, and minor changes in skin elasticity. Their skin fibroblasts show normal 

N-terminal procollagen protease activity however, the defect resides in the deletions of the exon that encodes the protease cleavage sites, thus preventing normal cleavage of the N-terminal propeptide. In animals, however, the defect is the N-terminal procollagen protease deficiency, which produces skin that is easily tom thus, the disease is known as dermatesparaxis. 

The collagen molecules formed by removal of the propeptides spontaneously assemble into fibrils. At this stage, the fibrils are still immature and lack tensile strength, which is acquired by cross-linking. The initial step in cross-link formation is the oxidative deamination of a-amino groups in certain lysyl and hydroxyly-syl residues catalyzed by lysyl oxidase. The enzyme is a copper-dependent (probably cupric) protein, and the reaction requires molecular oxygen and pyridoxal phosphate for full activity. Only native collagen fibrils function as substrates. 

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