Folding and conformational consequences of glycine to alanine replacements at different positions in a collagen model peptide

Manjiri Bhate, Xin Wang, Jean Baum, Barbara Brodsky

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The collagen model peptide T1-892 includes a C-terminal nucleation domain, (Gly-Pro-Hyp)4, and an N-terminal (Gly-X-Y)6 sequence taken from type I collagen. In osteogenesis imperfecta (OI) and other collagen diseases, single base mutations often convert one Gly to a larger residue, and T1-892 homologues modeling such mutations were synthesized with Gly to Ala substitutions in either the (Gly-Pro-Hyp)4 domain, Gly25Ala, or the (Gly-X-Y)6 domain, Gly10Ala. CD and NMR studies show the Gly10Ala peptide forms a normal triple-helix at the C-terminal end and propagates from the C- to the N-terminus until the Gly → Ala substitution is encountered. At this point, triple-helix folding is terminated and cannot be reinitiated, leaving a nonhelical N-terminus. A decreased thermal stability is observed as a result of the shorter length of the triple-helix. In contrast, introduction of the Gly to Ala replacement at position 25, in the nucleation domain, shifts the monomer/trimer equilibrium toward the monomer form. The increased monomer and lower trimer populations are reflected in the dramatic decrease in triple-helix content and stability. Unlike the Ala replacement at position 10, the Ala substitution in the (Gly-Pro-Hyp)4 region can still be incorporated into a triple-helix, but at a greatly decreased rate of folding, since the original efficient nucleation site is no longer operative. The specific consequences of Gly to Ala replacements in two distinctive sequences in this triple-helical peptide may help clarify the variability in OI clinical severity resulting from mutations at different sites along type I collagen chains.

Original languageEnglish (US)
Pages (from-to)6539-6547
Number of pages9
JournalBiochemistry
Volume41
Issue number20
DOIs
StatePublished - May 21 2002

All Science Journal Classification (ASJC) codes

  • Biochemistry

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