Cargando…
Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers
Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796876/ https://www.ncbi.nlm.nih.gov/pubmed/23695685 http://dx.doi.org/10.1038/ncomms2909 |
_version_ | 1782287544378982400 |
---|---|
author | Morris, Ryan J. Eden, Kym Yarwood, Reuben Jourdain, Line Allen, Rosalind J. MacPhee, Cait E. |
author_facet | Morris, Ryan J. Eden, Kym Yarwood, Reuben Jourdain, Line Allen, Rosalind J. MacPhee, Cait E. |
author_sort | Morris, Ryan J. |
collection | PubMed |
description | Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do not match experiments. Here we resolve this inconsistency using a combination of experimental kinetic measurements and computer simulations. We provide evidence for a structural transition that occurs at a critical fibril mass concentration, or ‘CFC’, above which fragmentation of fibrils is suppressed. Our simulations predict the formation of distinct fibril length distributions above and below the CFC, which we confirm by electron microscopy. These results point to a new picture of amyloid fibril growth in which structural transitions that occur during self-assembly have strong effects on the final population of aggregate species with small, and potentially cytotoxic, oligomers dominating for long periods of time at protein concentrations below the CFC. |
format | Online Article Text |
id | pubmed-3796876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-37968762013-10-15 Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers Morris, Ryan J. Eden, Kym Yarwood, Reuben Jourdain, Line Allen, Rosalind J. MacPhee, Cait E. Nat Commun Article Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do not match experiments. Here we resolve this inconsistency using a combination of experimental kinetic measurements and computer simulations. We provide evidence for a structural transition that occurs at a critical fibril mass concentration, or ‘CFC’, above which fragmentation of fibrils is suppressed. Our simulations predict the formation of distinct fibril length distributions above and below the CFC, which we confirm by electron microscopy. These results point to a new picture of amyloid fibril growth in which structural transitions that occur during self-assembly have strong effects on the final population of aggregate species with small, and potentially cytotoxic, oligomers dominating for long periods of time at protein concentrations below the CFC. 2013 /pmc/articles/PMC3796876/ /pubmed/23695685 http://dx.doi.org/10.1038/ncomms2909 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Morris, Ryan J. Eden, Kym Yarwood, Reuben Jourdain, Line Allen, Rosalind J. MacPhee, Cait E. Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title | Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title_full | Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title_fullStr | Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title_full_unstemmed | Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title_short | Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
title_sort | mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796876/ https://www.ncbi.nlm.nih.gov/pubmed/23695685 http://dx.doi.org/10.1038/ncomms2909 |
work_keys_str_mv | AT morrisryanj mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers AT edenkym mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers AT yarwoodreuben mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers AT jourdainline mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers AT allenrosalindj mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers AT macpheecaite mechanisticandenvironmentalcontroloftheprevalenceandlifetimeofamyloidoligomers |