title: Osteogenesis imperfecta model peptides: incorporation of residues replacing Gly within a triple helix achieved by renucleation and local flexibility.
abstract: Missense mutations, which replace one Gly with a larger residue in the repeating sequence of the type I collagen triple helix, lead to the hereditary bone disorder osteogenesis imperfecta (OI). Previous studies suggest that these mutations may interfere with triple-helix folding. NMR was used to investigate triple-helix formation in a series of model peptides where the residue replacing Gly, as well as the local sequence environment, was varied. NMR measurement of translational diffusion coefficients allowed the identification of partially folded species. When Gly was replaced by Ala, the Ala residue was incorporated into a fully folded triple helix, whereas replacement of Gly by Ser or Arg resulted in the presence of some partially folded species, suggesting a folding barrier. Increasing the triple-helix stability of the sequence N-terminal to a Gly-to-Ser replacement allowed complete triple-helix folding, whereas with the substitution of Arg, with its large side chain, the peptide achieved full folding only after flexible residues were introduced N-terminal to the mutation site. These studies shed light on the factors important for accommodation of Gly mutations within the triple helix and may relate to the varying severity of OI.
authors.affiliation: Department of Chemistry and Chemical Biology, BIOMAPS Institute, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Jianxi
authors.initials: J
authors.lastname: Xiao
authors.forename: Balaraman
authors.initials: B
authors.lastname: Madhan
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.forename: Barbara
authors.initials: B
authors.lastname: Brodsky
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004058:Diffusion; D005998:Glycine / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D010013:Osteogenesis Imperfecta / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D018583:Pliability; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D024042:Collagen Type I; D050505:Mutant Proteins; D010455:Peptides; D005998:Glycine