Synthetic, Register-Specific, AAB Heterotrimers to Investigate Single Point Glycine Mutations in Osteogenesis Imperfecta

• Published in: Biomacromolecules Vol. 17; no. 3; pp. 914 - 921
• Main Authors: Acevedo-Jake, Amanda M., Clements, Katherine A., Hartgerink, Jeffrey D.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.03.2016
• Subjects: Amino Acid Substitution; Collagen Type I - chemistry; Collagen Type I - genetics; Glycine - chemistry; Glycine - genetics; Molecular Dynamics Simulation; Oligopeptides - chemistry; Osteogenesis Imperfecta - genetics; Point Mutation; Protein Folding
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.5b01562

Osteogenesis imperfecta (OI) is a disease caused primarily by mutations of glycine in the standard (Xaa-Yaa-Gly) n repeat of a type I collagen triple helix. Type I collagen is an AAB heterotrimer which means that, depending on whether the A or B chain is mutated, the glycine substitution will appear once or twice. In this work we use designed axial charged pairs to self-assemble an AAB triple helix with controlled composition and register. We then substitute a single glycine of the B chain with alanine, serine, valine, aspartate, or arginine and assess the impact on the structure and folding of this OI mimic by CD, NMR, and restraint-guided modeling. We find that alanine and serine substitutions are tolerated, resulting in localized disruptions to the triple helix structure, while bulkier amino acids result in alternatively folded structures. This work demonstrates the potential of axial charged pairs to control the structure of low stability triple helices and also helps to elucidate the structure and folding challenges associated with OI-type mutations in collagen.