Folding defects in fibrillar collagens

Fibrillar collagens have a long triple helix in which glycine is in every t hird position for more than 1000 amino acids. The three chains of these mol ecules are assembled with specificity into several different molecules that have tissue-specific 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 t he bulk of the triple helix, all result in identifiable genetic disorders i n which the phenotype reflects the region of expression of the genes and th eir tissue-specific distribution. Mutations that result in changed amino-ac id sequences in any of these regions have different effects on folding and may have different phenotypic outcomes. Substitution for glycine residues i n the triple helical domains are among the most common effects of mutations , and the nature of the substituting residue and its location in the chain contribute to the effect on folding and also on the phenotype. More complex mutations, such as deletions or insertions of triple helix, also affect fo lding, probably because of alterations in helical pitch along the triple he lix. These mutations all interfere with the ability of these molecules to f orm the characteristic fibrillar array in the extracellular matrix and many result in intracellular retention of abnormal molecules.