The globular domain in the NH 2 -terminal propeptide (N-propeptide) of the pro␣1(I) chain is largely encoded by exon 2 of the Col1a1 gene and has been implicated in a number of processes that are involved in the biogenesis, maturation, and function of type I collagen. These include intracellular chain association, transcellular transport and secretion, proteolytic processing of the precursor, feedback regulation of synthesis, and control of fibrillogenesis. However, none of these proposed functions has been firmly established. To evaluate the function of this procollagen domain we have used a targeted mutagenesis approach to generate mice that lack exon 2 in the Col1a1 gene. Mouse lines were established on both a mixed 129 OlaHsd/Sv and C57BL/6 background and a pure 129 OlaHsd/Sv background. Adult mice on the mixed background are normal in appearance and are fertile. To the extent that they have been studied, procollagen synthesis, secretion, and proteolytic processing are normal in these mice, and collagen fibrillogenesis is only slightly altered. However, breeding of heterozygous mutant mice on the 129 background generated homozygous mutants at only 64% of the expected frequency. These findings suggest that although the Npropeptide is not essential for collagen biogenesis in mice it may play some essential role during embryonic development.Type I collagen is synthesized as a precursor, procollagen, with NH 2 -and COOH-terminal non-triple helical extensions (N-and C-propeptides) that are released extracellularly by limited proteolysis with procollagen N-and C-proteinases (1-4). The C-propeptide domain of procollagen participates in the association of the two pro␣1 and one pro␣2 chains to initiate triple helix formation from the COOH terminus of the protein (5-7).A number of functions have been proposed for the ␣1(I) N-propeptide in the biogenesis of type I collagen, including prevention of premature intracellular molecular association and facilitation of transcellular transport and secretion, conversion of procollagen to collagen, regulation of extracellular fibrillogenesis, and feedback regulation of procollagen synthesis. However, none of these functions has been established unequivocally, and some have been questioned. Lee et al. (8) studied the secretion of mutated type I procollagen, generated from human cDNA genes that were transfected into Chinese hamster lung, Mov-13, and COS-7 cells. Whereas wild-type (WT) 1 procollagen was secreted efficiently, proteins lacking either the entire N-propeptide (139 amino acids) or the majority of it (114 amino acids) were secreted poorly from Chinese hamster lung cells. In contrast, the WT and mutant proteins were secreted equally well by Mov-13 and COS-7 cells. Because Chinese hamster lung cells are epithelial-like, whereas Mov-13 and COS-7 cells are fibroblast-like, the failure of the former to secrete a collagen lacking N-propeptides may be unrelated to the structure of the protein. In all cases, triple helical assembly of the transfected gene products occurred nor...
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