Noncore residues influence the kinetics of functional TTR(105-115)-based amyloid fibril assembly

J Mol Biol. 2012 Aug 10;421(2-3):256-69. doi: 10.1016/j.jmb.2011.12.020. Epub 2011 Dec 16.


Mutations in the polypeptide sequence that forms the core structure of amyloid fibrils are known to impact on fibril assembly and stability but the effect of changes on noncore residues, particularly relating to functionalized fibrils where the fibril core is preserved, has not been systematically examined. In this study, the short peptide sequence TTR(105-115) (also known as TTR1) and the functionalized variants TTR1-RGD and TTR1-RAD are used as a model system to investigate the effect of noncore residues on the kinetics of fibril assembly. The noncore residues in TTR1-RGD and TTR1-RAD influence the rate of fibril assembly in non-seeded samples with the glycine residue at position 15 increasing the rate of aggregation compared to alanine. Mature TTR1-RGD fibrils were also found to fragment more readily, indicating possible differences in mechanical properties. Fragments of each type of fibril are capable of self- and cross-seeding, generating fibrils with a highly similar cross-β core structure. The similar rates of assembly observed for self-seeded samples reflect the similar free energy of elongation calculated for these peptides, while the morphology of cross-seeded fibrils is determined by the properties of the monomeric peptide and its macromolecular arrangement within the protofilaments and fibrils. These findings illustrate that noncore residues impact on fibril formation and fibril properties and demonstrate that the influence of noncore residues should be considered when designing sequences for the production of self-assembling functional fibrillar materials.

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Kinetics
  • Microscopy, Electron, Transmission
  • Models, Chemical
  • Molecular Sequence Data
  • Prealbumin / chemistry*
  • Prealbumin / genetics
  • X-Ray Diffraction


  • Amyloid
  • Prealbumin