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Synthetic, register-specific, AAB heterotrimers to investigate single point glycine mutations in osteogenesis imperfecta

Synthetic, register-specific, AAB heterotrimers to investigate single point glycine mutations in osteogenesis imperfecta
Synthetic, register-specific, AAB heterotrimers to investigate single point glycine mutations in osteogenesis imperfecta
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.
1525-7797
914-921
Acevedo-Jake, Amanda M.
648b12e3-763b-4e0b-bf33-abf4f85be1ef
Clements, Katherine A.
c450795d-63da-45b6-bf68-2f76326931b9
Hartgerink, Jeffrey D.
37f5e1c8-1280-4133-8584-b327d6fcaaeb
Acevedo-Jake, Amanda M.
648b12e3-763b-4e0b-bf33-abf4f85be1ef
Clements, Katherine A.
c450795d-63da-45b6-bf68-2f76326931b9
Hartgerink, Jeffrey D.
37f5e1c8-1280-4133-8584-b327d6fcaaeb

Acevedo-Jake, Amanda M., Clements, Katherine A. and Hartgerink, Jeffrey D. (2016) Synthetic, register-specific, AAB heterotrimers to investigate single point glycine mutations in osteogenesis imperfecta. Biomacromolecules, 17 (3), 914-921. (doi:10.1021/acs.biomac.5b01562).

Record type: Article

Abstract

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.

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e-pub ahead of print date: 9 February 2016
Published date: 14 March 2016

Identifiers

Local EPrints ID: 434655
URI: http://eprints.soton.ac.uk/id/eprint/434655
ISSN: 1525-7797
PURE UUID: c193ca71-aa04-4dda-8fa8-f838c08a6d4f

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Date deposited: 04 Oct 2019 16:30
Last modified: 04 Oct 2019 16:30

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