title: Sequence dependence of renucleation after a Gly mutation in model collagen peptides.
abstract: Missense mutations in the collagen triple helix that replace one Gly residue in the (Gly-X-Y)(n) repeating pattern by a larger amino acid have been shown to delay triple helix folding. One hypothesis is that such mutations interfere with the C- to N-terminal directional propagation and that the identity of the residues immediately N-terminal to the mutation site may determine the delay time and the degree of clinical severity. Model peptides are designed to clarify the role of tripeptide sequences N-terminal to the mutation site, with respect to length, stability, and nucleation propensity, to complete triple helix folding. Two sets of peptides with different N-terminal sequences, one with the natural sequence alpha1(I) 886-900, which is just adjacent to the Gly(901) mutation, and one with a GPO(GAO)(3) sequence, which occurs at alpha1(I) 865-879, are studied by CD and NMR. Placement of the five tripeptides of the natural alpha1(I) collagen sequence N-terminal to the Gly to Ala mutation site results in a peptide that is folded only C-terminal to the mutation site. In contrast, the presence of the Hyp-rich sequence GPO(GAO)(3) N-terminal to the mutation allows complete refolding in the presence of the mutation. The completely folded peptide contains an ordered central region with unusual hydrogen bonding while maintaining standard triple helix structure at the N- and C-terminal ends. These peptide results suggest that the location and sequences of downstream regions favorable for renucleation could be the key factor in the completion of a triple helix N-terminal to a mutation.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hyde
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bryan
authors.forename: Barbara
authors.initials: B
authors.lastname: Brodsky
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry*; D024042:Collagen Type I / Q000737:chemistry; D000090602:Collagen Type I, alpha 1 Chain; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010455:Peptides; D003094:Collagen; D005998:Glycine