Two cysteine substitutions in procollagen I: a glycine replacement near the N-terminus of alpha 1(I) chain causes lethal osteogenesis imperfecta and a glycine replacement in the alpha 2(I) chain markedly destabilizes the triple helix.
Cultured skin fibroblasts were examined from two probands with type II (lethal) osteogenesis imperfecta. One proband had a single base mutation which converted the glycine codon at position alpha 1-244 in the alpha 1(I) chain of procollagen I into a cysteine codon whereas the other had a similar mutation that converted the glycine codon at position alpha 2-787 of the alpha 2(I) chain into a cysteine codon. Both mutations produced post-translational overmodification of procollagen I. The Cys alpha 1-244 mutation, however, had a minimal effect on the thermal stability or secretion of the protein whereas the Cys alpha 2-787 mutation markedly decreased the thermal stability and, apparently as a result, essentially none of the mutated protein was secreted. The results provide clear exceptions to two previous generalizations about the position-specificity of glycine substitutions in procollagen I.
Fertala
A
A
Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Westerhausen
A
A
Morris
G
G
Rooney
J E
JE
Prockop
D J
DJ
D001483:Base Sequence; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics*; D004247:DNA; D005347:Fibroblasts / Q000737:chemistry; D005804:Genes, Lethal; D005998:Glycine / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D011347:Procollagen / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics
D011347:Procollagen; D012333:RNA, Messenger; D004247:DNA; D003545:Cysteine; D005998:Glycine