Thermal stability and folding of the collagen triple helix and the effects of mutations in osteogenesis imperfecta on the triple helix of type I collagen

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Abstract
Osteogenesis imperfecta (OI) is an inherited disease in which 90% of the cases result from mutations in the 2 genes, proα1 and proα2, coding for type I collagen. Type I collagen is a trimeric molecule, (α1)2α2, which is dominated both structurally and functionally by the 300 nm triple‐helical domain. Most OI mutations occur in this domain and almost all point mutations result in the substitution of other amino acids for the obligate glycine which occurs at every third residue. The phenotypic effects of these mutations are frequently attributed in part to alterations in the stability and rate of folding of the triple helix. In order to better understand the relationship between glycine substituions and stability we review current concepts of the forces governing triple helical stability, denaturational and predenaturational unfolding, and the techniques of measuring stability. From observations on the stability of several collagen types as well as synthetic tripeptides, we present a model for stability based on the contribution of individual and neighboring tripeptide units to the local stability. Although in preliminary form, this empirical model can account for the observed shifts in the Tm of many of the point mutations described. The folding of the triple helix is reviewed. The involvement of peptidyl prolyl cis‐trans isomerase in this process in vivo is demonstrated by the inhibition of collagen folding in fibroblasts by cyclosporin A. An hypothesis based on the relationship between the thermal stability at the site of mutation and the propensity for renucleation of folding is proposed.