Sequence dependence of renucleation after a Gly mutation in model collagen peptides

Timothy J. Hyde, Michael A. Bryan, Barbara Brodsky, Jean Baum

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39 Scopus citations

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 α1(I) 886-900, which is just adjacent to the Gly901 mutation, and one with a GPO(GAO)3 sequence, which occurs at α1(I) 865-879, are studied by CD and NMR. Placement of the five tripeptides of the natural α1(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.

Original languageAmerican English
Pages (from-to)36937-36943
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number48
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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