20235194

pubmed:Citation

1

Osteogenesis imperfecta (OI), a disorder characterized by fragile bones, is often a consequence of missense mutations in type I collagen, which change one Gly in the repeating (Gly-Xaa-Yaa)(n) sequence to a larger amino acid. The impact of local environment and the identity of the residue replacing Gly were investigated using two sets of triple-helical peptides. Gly mutations in the highly stable (Pro-Hyp-Gly)(10) system are compared with mutations in T1-865 peptides where the mutation is located within a less stable natural collagen sequence. Replacement of a Gly residue by Ala, Ser, or Arg leads to significant triple-helical destabilization in both peptide systems. The loss of stability (?T(m) ) due to a Gly to Ala or Gly to Ser change was greater in the more rigid (Pro-Hyp-Gly)(10) peptides than in the T1-865 set, as expected. But the final T(m) values, which may be the more biologically meaningful parameters, were higher for the (Pro-Hyp-Gly)(10) mutation peptides than for the corresponding T1-865 mutation peptides. In both peptide environments, a Gly to Arg replacement prevented the formation of a fully folded triple-helix. Monitoring of folding by differential scanning calorimetry showed a lower stability species as well as the fully folded triple-helical molecules for T1-865 peptides with Gly to Ala or Ser replacements, and this lower stability species disappears as a function of time. The difficulty in propagation through a mutation site in T1-865 peptides may relate to the delayed folding seen in OI collagens and indicates a dependence of folding mechanism on the local sequence environment.

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pubmed-author:BrodskyBarbaraB, pubmed-author:BryanMichael AMA, pubmed-author:ChengHaimingH

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pubmed-meshheading:20235194-Amino Acid Sequence, pubmed-meshheading:20235194-Amino Acid Substitution, pubmed-meshheading:20235194-Arginine, pubmed-meshheading:20235194-Calorimetry, Differential Scanning, pubmed-meshheading:20235194-Circular Dichroism, pubmed-meshheading:20235194-Collagen Type I, pubmed-meshheading:20235194-Glycine, pubmed-meshheading:20235194-Humans, pubmed-meshheading:20235194-Molecular Sequence Data, pubmed-meshheading:20235194-Mutation, pubmed-meshheading:20235194-Osteogenesis Imperfecta, pubmed-meshheading:20235194-Peptides, pubmed-meshheading:20235194-Protein Conformation, pubmed-meshheading:20235194-Protein Folding, pubmed-meshheading:20235194-Protein Stability, pubmed-meshheading:20235194-Protein Structure, Secondary, pubmed-meshheading:20235194-Protein Unfolding, pubmed-meshheading:20235194-Thermodynamics

Sequence environment of mutation affects stability and folding in collagen model peptides of osteogenesis imperfecta.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural