---
_id: '10336'
abstract:
- lang: eng
  text: Biological membranes can dramatically accelerate the aggregation of normally
    soluble protein molecules into amyloid fibrils and alter the fibril morphologies,
    yet the molecular mechanisms through which this accelerated nucleation takes place
    are not yet understood. Here, we develop a coarse-grained model to systematically
    explore the effect that the structural properties of the lipid membrane and the
    nature of protein–membrane interactions have on the nucleation rates of amyloid
    fibrils. We identify two physically distinct nucleation pathways—protein-rich
    and lipid-rich—and quantify how the membrane fluidity and protein–membrane affinity
    control the relative importance of those molecular pathways. We find that the
    membrane’s susceptibility to reshaping and being incorporated into the fibrillar
    aggregates is a key determinant of its ability to promote protein aggregation.
    We then characterize the rates and the free-energy profile associated with this
    heterogeneous nucleation process, in which the surface itself participates in
    the aggregate structure. Finally, we compare quantitatively our data to experiments
    on membrane-catalyzed amyloid aggregation of α-synuclein, a protein implicated
    in Parkinson’s disease that predominately nucleates on membranes. More generally,
    our results provide a framework for understanding macromolecular aggregation on
    lipid membranes in a broad biological and biotechnological context.
acknowledgement: We thank T. C. T. Michaels for reading the manuscript. This work
  was supported by the Academy of Medical Science (J.K. and A.Š.), the Cambridge Center
  for Misfolding Diseases (T.P.J.K.), the Biotechnology and Biological Sciences Research
  Council (T.P.J.K.), the Frances and Augustus Newman Foundation (T.P.J.K.), the European
  Research Council Grant PhysProt Agreement 337969, the Wellcome Trust (A.Š. and T.P.J.K.),
  the Royal Society (A.Š.), the Medical Research Council (J.K. and A.Š.), and the
  UK Materials and Molecular Modeling Hub for computational resources, which is partially
  funded by Engineering and Physical Sciences Research Council Grant EP/P020194/1.
article_processing_charge: No
article_type: original
author:
- first_name: Johannes
  full_name: Krausser, Johannes
  last_name: Krausser
- first_name: Tuomas P. J.
  full_name: Knowles, Tuomas P. J.
  last_name: Knowles
- first_name: Anđela
  full_name: Šarić, Anđela
  id: bf63d406-f056-11eb-b41d-f263a6566d8b
  last_name: Šarić
  orcid: 0000-0002-7854-2139
citation:
  ama: Krausser J, Knowles TPJ, Šarić A. Physical mechanisms of amyloid nucleation
    on fluid membranes. <i>Proceedings of the National Academy of Sciences</i>. 2020;117(52):33090-33098.
    doi:<a href="https://doi.org/10.1073/pnas.2007694117">10.1073/pnas.2007694117</a>
  apa: Krausser, J., Knowles, T. P. J., &#38; Šarić, A. (2020). Physical mechanisms
    of amyloid nucleation on fluid membranes. <i>Proceedings of the National Academy
    of Sciences</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.2007694117">https://doi.org/10.1073/pnas.2007694117</a>
  chicago: Krausser, Johannes, Tuomas P. J. Knowles, and Anđela Šarić. “Physical Mechanisms
    of Amyloid Nucleation on Fluid Membranes.” <i>Proceedings of the National Academy
    of Sciences</i>. National Academy of Sciences, 2020. <a href="https://doi.org/10.1073/pnas.2007694117">https://doi.org/10.1073/pnas.2007694117</a>.
  ieee: J. Krausser, T. P. J. Knowles, and A. Šarić, “Physical mechanisms of amyloid
    nucleation on fluid membranes,” <i>Proceedings of the National Academy of Sciences</i>,
    vol. 117, no. 52. National Academy of Sciences, pp. 33090–33098, 2020.
  ista: Krausser J, Knowles TPJ, Šarić A. 2020. Physical mechanisms of amyloid nucleation
    on fluid membranes. Proceedings of the National Academy of Sciences. 117(52),
    33090–33098.
  mla: Krausser, Johannes, et al. “Physical Mechanisms of Amyloid Nucleation on Fluid
    Membranes.” <i>Proceedings of the National Academy of Sciences</i>, vol. 117,
    no. 52, National Academy of Sciences, 2020, pp. 33090–98, doi:<a href="https://doi.org/10.1073/pnas.2007694117">10.1073/pnas.2007694117</a>.
  short: J. Krausser, T.P.J. Knowles, A. Šarić, Proceedings of the National Academy
    of Sciences 117 (2020) 33090–33098.
date_created: 2021-11-25T15:07:09Z
date_published: 2020-12-16T00:00:00Z
date_updated: 2021-11-25T15:35:58Z
day: '16'
doi: 10.1073/pnas.2007694117
extern: '1'
external_id:
  pmid:
  - '33328273'
intvolume: '       117'
issue: '52'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://www.biorxiv.org/content/10.1101/2019.12.22.886267v2
month: '12'
oa: 1
oa_version: Published Version
page: 33090-33098
pmid: 1
publication: Proceedings of the National Academy of Sciences
publication_identifier:
  eissn:
  - 1091-6490
  issn:
  - 0027-8424
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
scopus_import: '1'
status: public
title: Physical mechanisms of amyloid nucleation on fluid membranes
type: journal_article
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
volume: 117
year: '2020'
...