Folding defects in fibrillar collagens

Abstract

Fibrillar collagens have a long triple helix in which glycine is in every third position for more than 1000 amino acids. The three chains of these molecules are assembled with speci¢city into several di¡erent molecules that have tissue-speci¢c distribution. Mutations that alter folding of either the carboxy-terminal globular peptides that direct chain association, or of the regions of the triple helix that are important for nucleation, or of the bulk of the triple helix, all result in identi¢able genetic disorders in which the phenotype re£ects the region of expression of the genes and their tissue-speci¢c distribution. Mutations that result in changed amino-acid sequences in any of these regions have di¡erent e¡ects on folding and may have di¡erent phenotypic outcomes. Substitution for glycine residues in the triple helical domains are among the most common e¡ects of mutations, and the nature of the substituting residue and its location in the chain contribute to the e¡ect on folding and also on the phenotype. More complex mutations, such as deletions or insertions of triple helix, also a¡ect folding, probably because of alterations in helical pitch along the triple helix. These mutations all interfere with the ability of these molecules to form the characteristic ¢brillar array in the extracellular matrix and many result in intracellular retention of abnormal molecules.

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains

“…These two parameters have been chosen, since there exists evidence in the literature that these physical properties are related to the severity degree of the OI disease, as pointed out in earlier work. 8,9 We find that the molecule's stiffness can be expressed as a function of these two factors. This is achieved in an empirical relation with five parameters, in a simple model:…”

“…In particular it has been observed that large and charged residues generally lead to more severe OI types. [7][8][9] Here we have shown that the local mechanical properties of single tropocollagen molecules can be predicted based on the physical properties of the replacing residue.…”

“…Some trends are apparent, such as OI severity increasing with an amino to carboxyl terminal orientation and with substitution by large and charged amino acids. [7][8][9] At present, however, genotype-phenotype correlations are too weak to accurately predict the phenotypic effect of a particular glycine mutation. Indeed, the answer to the question how a single point mutation in the tropocollagen molecule can cause the failure of the entire skeletal system still remains a mystery.…”

Cartilage Extracellular Matrix Integrity and OA

“…Similarly in the 1990s, particular families were discovered to have missense mutation (R519C) causing the production of abnormal type II collagen pro-alphachains. These alpha chains formed protein dimers leading to mild chondrodysplasia followed by a unique form of familial OA (Byers, 2001;Eyre et al, 1991;Pun et al, 1994;Bleasel et al, 1998).…”

“…While heterozygous deletion of this gene in mice show a minimal phenotype, complete homozygous deletion predictably causes severe cartilage tissue disorganization and death shortly after birth . In addition to being linked to the development of degenerative joint diseases such (Byers, 2001). A mutation in the alpha helical domain causing a substitution of a glycine codon with a larger amino acid has been shown to disrupt proper alpha helix formation of type II collagen leading to severe chondrodysplasias and a significant reduction in cartilage tissue stability (Kuivaniemi et al, 1997;Prockop et al, 1997).…”