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Sequence environment of mutation affects stability and folding in collagen model peptides of osteogenesis imperfecta
Author(s) -
Bryan Michael A.,
Cheng Haiming,
Brodsky Barbara
Publication year - 2011
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21432
Subject(s) - chemistry , osteogenesis imperfecta , peptide , missense mutation , mutation , triple helix , peptide sequence , amino acid , circular dichroism , folding (dsp implementation) , stereochemistry , biochemistry , biophysics , gene , biology , anatomy , electrical engineering , engineering
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 (ΔT 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. © 2010 Wiley Periodicals, Inc.Biopolymers (Pept Sci) 96: 4–13, 2011.