DELAYED TRIPLE-HELIX FORMATION OF MUTANT COLLAGEN FROM PATIENTS WITH OSTEOGENESIS IMPERFECTA

被引:107
作者
RAGHUNATH, M [1 ]
BRUCKNER, P [1 ]
STEINMANN, B [1 ]
机构
[1] SWISS FED INST TECHNOL,DEPT BIOCHEM 1,CH-8092 ZURICH,SWITZERLAND
关键词
COLLAGEN I; FOLDING; MUTATION; FIBROBLAST; OSTEOGENESIS IMPERFECTA;
D O I
10.1006/jmbi.1994.1199
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The kinetics of triple helix formation of procollagen I were measured in normal human fibroblast cultures and cell strains from six patients with osteogenesis imperfecta (OI), a heritable connective tissue disorder. After a 4-minute pulse-labelling with [35S]methionine, the appearance of protease-resistant and thus helical collagen molecules was followed for variable chase times. In control cells, 50% of the molecules were fully triple-helical after 14 minutes. In the six OI cell strains harbouring a single Gly → Cys substitution at positions 94, 223, 526, 691 and 988 in the helical domain of the α1(I)-chain, formation of full-length protease-resistant molecules containing two mutant α1(I)-chains as judged by the appearance of disulphide-linked α1(I)-dimers was delayed by 5 to 60 minutes. The delay inversely correlated with the thermal stability of abnormal collagen molecules containing α1(I)-dimers. Folding time and melting temperature of procollagen I in the sixth cell strain with a Gly → Cys substitution at position 1017, outside the triple helical region in the C-terminal telopeptide, were normal. Here, we demonstrate the hitherto postulated delay in the zipper-like folding of collagen molecules harbouring Gly → Cys substitutions in the α1(I)-chain affecting the helical part of the molecule.
引用
收藏
页码:940 / 949
页数:10
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