Structural Heterogeneity of Type I Collagen Triple Helix and Its Role in Osteogenesis Imperfecta

• Published in: The Journal of biological chemistry 2008-02, Vol.283 (8), p.4787-4798
• Main Authors: Makareeva, Elena, Mertz, Edward L., Kuznetsova, Natalia V., Sutter, Mary B., DeRidder, Angela M., Cabral, Wayne A., Barnes, Aileen M., McBride, Daniel J., Marini, Joan C., Leikin, Sergey
• Format: Article
• Language: English
• Subjects: Circular Dichroism; Collagen Type I - chemistry; Humans; Osteogenesis Imperfecta; Peptide Mapping; Protein Folding; Protein Structure, Quaternary; Protein Structure, Secondary
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M705773200

We investigated regions of different helical stability within human type I collagen and discussed their role in intermolecular interactions and osteogenesis imperfecta (OI). By differential scanning calorimetry and circular dichroism, we measured and mapped changes in the collagen melting temperature (ΔTm) for 41 different Gly substitutions from 47 OI patients. In contrast to peptides, we found no correlations of ΔTm with the identity of the substituting residue. Instead, we observed regular variations in ΔTm with the substitution location in different triple helix regions. To relate the ΔTm map to peptide-based stability predictions, we extracted the activation energy of local helix unfolding (ΔG‡) from the reported peptide data. We constructed the ΔG‡ map and tested it by measuring the H-D exchange rate for glycine NH residues involved in interchain hydrogen bonds. Based on the ΔTm and ΔG‡ maps, we delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the ΔTm map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the α1(I) chain.