NUCLEAR-MAGNETIC-RESONANCE SHOWS ASYMMETRIC LOSS OF TRIPLE-HELIX IN PEPTIDES MODELING A COLLAGEN MUTATION IN BRITTLE BONE-DISEASE

TO investigate a human folding disease, NMR studies were carried out o n collagen-like peptides to define the structural consequences of a si ngle amino acid change found in patients with osteogenesis imperfecta (OI), a disease characterized by fragile bones. One peptide included a normal collagen sequence, while a second peptide included a Gly --> S er substitution as found in a nonlethal case of OI. Residue specific i nternal dynamics and conformational studies indicate that the normal c ollagen-like sequence forms a triple helix which is rigid along its en tire length. The introduction of a Gly --> Ser substitution induces an asymmetric disruption of the uniform triple helix. While the C-termin al end of the peptide retains the triple helix, the Ser substitution s ite and residues N-terminal to it exhibit the mobility of a random cha in. This equilibrium state indicates that a Gly substitution can termi nate the C to N propagation of the triple helix and suggests that renu cleation is required for folding to continue. Defective folding has be en implicated in brittle bone disease, and these results begin to char acterize the folding process in OI collagens. OI collagen studies may also provide insights about defective protein folding, assembly, and a ggregation in other human diseases.