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

By Amanda M. Acevedo-Jake (1407865), Katherine A. Clements (1407862) and Jeffrey D. Hartgerink (1321893)

Abstract

Osteogenesis imperfecta (OI) is a disease caused primarily by mutations of glycine in the standard (Xaa-Yaa-Gly)<sub><i>n</i></sub> 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

Topics: Biophysics, Biochemistry, Microbiology, Genetics, Molecular Biology, Immunology, Cancer, Hematology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, alanine, Investigate Single Point Glycine Mutations, AAB, collagen, Osteogenesis ImperfectaOsteogenesis imperfecta, glycine, mutation, serine, helix, B chain, NMR, OI, substitution
Year: 2016
DOI identifier: 10.1021/acs.biomac.5b01562.s001
OAI identifier: oai:figshare.com:article/2077213
Provided by: FigShare
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