---
_id: '12152'
abstract:
- lang: eng
text: ESCRT-III filaments are composite cytoskeletal polymers that can constrict
and cut cell membranes from the inside of the membrane neck. Membrane-bound ESCRT-III
filaments undergo a series of dramatic composition and geometry changes in the
presence of an ATP-consuming Vps4 enzyme, which causes stepwise changes in the
membrane morphology. We set out to understand the physical mechanisms involved
in translating the changes in ESCRT-III polymer composition into membrane deformation.
We have built a coarse-grained model in which ESCRT-III polymers of different
geometries and mechanical properties are allowed to copolymerise and bind to a
deformable membrane. By modelling ATP-driven stepwise depolymerisation of specific
polymers, we identify mechanical regimes in which changes in filament composition
trigger the associated membrane transition from a flat to a buckled state, and
then to a tubule state that eventually undergoes scission to release a small cargo-loaded
vesicle. We then characterise how the location and kinetics of polymer loss affects
the extent of membrane deformation and the efficiency of membrane neck scission.
Our results identify the near-minimal mechanical conditions for the operation
of shape-shifting composite polymers that sever membrane necks.
acknowledgement: "A.S . received an award from European Research Council (https://erc.europa.eu,
“NEPA\"\r\n802960), and an award from the Royal Society (https://royalsociety.org,
UF160266). L. H.-K.\r\nreceived an award from the Biotechnology and Biological Sciences
Research Council (https://\r\nwww.ukri.org/councils/bbsrc/). E. L. received an award
from the University College London (https://www.ucl.ac.uk/biophysics/news/2022/feb/applications-biop-brian-duff-and-ipls-summerundergraduate-studentships-now-open,
Brian Duff Undergraduate Summer Research Studentship). B.B. and A.S. received an
award from Volkswagen Foundation https://www.volkswagenstiftung.de/en/foundation,
Az 96727), and an award from Medical Research Council (https://www.ukri.org/councils/mrc,
MC_CF1226). A. R. received an\r\naward from the Swiss National Fund for Research
(https://www.snf.ch/en, 31003A_130520,\r\n31003A_149975, and 31003A_173087) and
an award from the European Research Council\r\nConsolidator (https://erc.europa.eu,
311536). The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript."
article_number: e1010586
article_processing_charge: No
article_type: original
author:
- first_name: Xiuyun
full_name: Jiang, Xiuyun
last_name: Jiang
- first_name: Lena
full_name: Harker-Kirschneck, Lena
last_name: Harker-Kirschneck
- first_name: Christian Eduardo
full_name: Vanhille-Campos, Christian Eduardo
id: 3adeca52-9313-11ed-b1ac-c170b2505714
last_name: Vanhille-Campos
- first_name: Anna-Katharina
full_name: Pfitzner, Anna-Katharina
last_name: Pfitzner
- first_name: Elene
full_name: Lominadze, Elene
last_name: Lominadze
- first_name: Aurélien
full_name: Roux, Aurélien
last_name: Roux
- first_name: Buzz
full_name: Baum, Buzz
last_name: Baum
- first_name: Anđela
full_name: Šarić, Anđela
id: bf63d406-f056-11eb-b41d-f263a6566d8b
last_name: Šarić
orcid: 0000-0002-7854-2139
citation:
ama: Jiang X, Harker-Kirschneck L, Vanhille-Campos CE, et al. Modelling membrane
reshaping by staged polymerization of ESCRT-III filaments. PLOS Computational
Biology. 2022;18(10). doi:10.1371/journal.pcbi.1010586
apa: Jiang, X., Harker-Kirschneck, L., Vanhille-Campos, C. E., Pfitzner, A.-K.,
Lominadze, E., Roux, A., … Šarić, A. (2022). Modelling membrane reshaping by staged
polymerization of ESCRT-III filaments. PLOS Computational Biology. Public
Library of Science. https://doi.org/10.1371/journal.pcbi.1010586
chicago: Jiang, Xiuyun, Lena Harker-Kirschneck, Christian Eduardo Vanhille-Campos,
Anna-Katharina Pfitzner, Elene Lominadze, Aurélien Roux, Buzz Baum, and Anđela
Šarić. “Modelling Membrane Reshaping by Staged Polymerization of ESCRT-III Filaments.”
PLOS Computational Biology. Public Library of Science, 2022. https://doi.org/10.1371/journal.pcbi.1010586.
ieee: X. Jiang et al., “Modelling membrane reshaping by staged polymerization
of ESCRT-III filaments,” PLOS Computational Biology, vol. 18, no. 10. Public
Library of Science, 2022.
ista: Jiang X, Harker-Kirschneck L, Vanhille-Campos CE, Pfitzner A-K, Lominadze
E, Roux A, Baum B, Šarić A. 2022. Modelling membrane reshaping by staged polymerization
of ESCRT-III filaments. PLOS Computational Biology. 18(10), e1010586.
mla: Jiang, Xiuyun, et al. “Modelling Membrane Reshaping by Staged Polymerization
of ESCRT-III Filaments.” PLOS Computational Biology, vol. 18, no. 10, e1010586,
Public Library of Science, 2022, doi:10.1371/journal.pcbi.1010586.
short: X. Jiang, L. Harker-Kirschneck, C.E. Vanhille-Campos, A.-K. Pfitzner, E.
Lominadze, A. Roux, B. Baum, A. Šarić, PLOS Computational Biology 18 (2022).
date_created: 2023-01-12T12:08:10Z
date_published: 2022-10-17T00:00:00Z
date_updated: 2023-08-04T09:03:21Z
day: '17'
ddc:
- '570'
department:
- _id: AnSa
doi: 10.1371/journal.pcbi.1010586
ec_funded: 1
external_id:
isi:
- '000924885500005'
file:
- access_level: open_access
checksum: bada6a7865e470cf42bbdfa67dd471d2
content_type: application/pdf
creator: dernst
date_created: 2023-01-24T10:45:01Z
date_updated: 2023-01-24T10:45:01Z
file_id: '12359'
file_name: 2022_PLoSCompBio_Jiang.pdf
file_size: 2641067
relation: main_file
success: 1
file_date_updated: 2023-01-24T10:45:01Z
has_accepted_license: '1'
intvolume: ' 18'
isi: 1
issue: '10'
keyword:
- Computational Theory and Mathematics
- Cellular and Molecular Neuroscience
- Genetics
- Molecular Biology
- Ecology
- Modeling and Simulation
- Ecology
- Evolution
- Behavior and Systematics
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
project:
- _id: eba2549b-77a9-11ec-83b8-a81e493eae4e
call_identifier: H2020
grant_number: '802960'
name: 'Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines'
- _id: eba0f67c-77a9-11ec-83b8-cc8501b3e222
grant_number: '96752'
name: 'The evolution of trafficking: from archaea to eukaryotes'
publication: PLOS Computational Biology
publication_identifier:
issn:
- 1553-7358
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
related_material:
link:
- relation: software
url: https://github.com/sharonJXY/3-filament-model
scopus_import: '1'
status: public
title: Modelling membrane reshaping by staged polymerization of ESCRT-III filaments
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 18
year: '2022'
...
---
_id: '12251'
abstract:
- lang: eng
text: Amyloid formation is linked to devastating neurodegenerative diseases, motivating
detailed studies of the mechanisms of amyloid formation. For Aβ, the peptide associated
with Alzheimer’s disease, the mechanism and rate of aggregation have been established
for a range of variants and conditions in vitro and
in bodily fluids. A key outstanding question is how the relative stabilities of
monomers, fibrils and intermediates affect each step in the fibril formation process.
By monitoring the kinetics of aggregation of Aβ42, in the presence of urea or
guanidinium hydrochloride (GuHCl), we here determine the rates of the underlying
microscopic steps and establish the importance of changes in relative stability
induced by the presence of denaturant for each individual step. Denaturants shift
the equilibrium towards the unfolded state of each species. We find that a non-ionic
denaturant, urea, reduces the overall aggregation rate, and that the effect on
nucleation is stronger than the effect on elongation. Urea reduces the rate of
secondary nucleation by decreasing the coverage of fibril surfaces and the rate
of nucleus formation. It also reduces the rate of primary nucleation, increasing
its reaction order. The ionic denaturant, GuHCl, accelerates the aggregation at
low denaturant concentrations and decelerates the aggregation at high denaturant
concentrations. Below approximately 0.25 M GuHCl, the screening of repulsive electrostatic
interactions between peptides by the charged denaturant dominates, leading to
an increased aggregation rate. At higher GuHCl concentrations, the electrostatic
repulsion is completely screened, and the denaturing effect dominates. The results
illustrate how the differential effects of denaturants on stability of monomer,
oligomer and fibril translate to differential effects on microscopic steps, with
the rate of nucleation being most strongly reduced.
acknowledgement: This work was supported by grants from the Swedish Research Council
(grant no. 2015-00143) and the European Research Council (grant no. 340890).
article_number: '943355'
article_processing_charge: No
article_type: original
author:
- first_name: Tanja
full_name: Weiffert, Tanja
last_name: Weiffert
- first_name: Georg
full_name: Meisl, Georg
last_name: Meisl
- first_name: Samo
full_name: Curk, Samo
last_name: Curk
- first_name: Risto
full_name: Cukalevski, Risto
last_name: Cukalevski
- first_name: Anđela
full_name: Šarić, Anđela
id: bf63d406-f056-11eb-b41d-f263a6566d8b
last_name: Šarić
orcid: 0000-0002-7854-2139
- first_name: Tuomas P. J.
full_name: Knowles, Tuomas P. J.
last_name: Knowles
- first_name: Sara
full_name: Linse, Sara
last_name: Linse
citation:
ama: Weiffert T, Meisl G, Curk S, et al. Influence of denaturants on amyloid β42
aggregation kinetics. Frontiers in Neuroscience. 2022;16. doi:10.3389/fnins.2022.943355
apa: Weiffert, T., Meisl, G., Curk, S., Cukalevski, R., Šarić, A., Knowles, T. P.
J., & Linse, S. (2022). Influence of denaturants on amyloid β42 aggregation
kinetics. Frontiers in Neuroscience. Frontiers Media. https://doi.org/10.3389/fnins.2022.943355
chicago: Weiffert, Tanja, Georg Meisl, Samo Curk, Risto Cukalevski, Anđela Šarić,
Tuomas P. J. Knowles, and Sara Linse. “Influence of Denaturants on Amyloid Β42
Aggregation Kinetics.” Frontiers in Neuroscience. Frontiers Media, 2022.
https://doi.org/10.3389/fnins.2022.943355.
ieee: T. Weiffert et al., “Influence of denaturants on amyloid β42 aggregation
kinetics,” Frontiers in Neuroscience, vol. 16. Frontiers Media, 2022.
ista: Weiffert T, Meisl G, Curk S, Cukalevski R, Šarić A, Knowles TPJ, Linse S.
2022. Influence of denaturants on amyloid β42 aggregation kinetics. Frontiers
in Neuroscience. 16, 943355.
mla: Weiffert, Tanja, et al. “Influence of Denaturants on Amyloid Β42 Aggregation
Kinetics.” Frontiers in Neuroscience, vol. 16, 943355, Frontiers Media,
2022, doi:10.3389/fnins.2022.943355.
short: T. Weiffert, G. Meisl, S. Curk, R. Cukalevski, A. Šarić, T.P.J. Knowles,
S. Linse, Frontiers in Neuroscience 16 (2022).
date_created: 2023-01-16T09:56:43Z
date_published: 2022-09-20T00:00:00Z
date_updated: 2023-08-04T09:48:56Z
day: '20'
ddc:
- '570'
department:
- _id: AnSa
doi: 10.3389/fnins.2022.943355
external_id:
isi:
- '000866287100001'
file:
- access_level: open_access
checksum: e67d16113ffb4fb4fa38a183d169f210
content_type: application/pdf
creator: dernst
date_created: 2023-01-30T09:15:13Z
date_updated: 2023-01-30T09:15:13Z
file_id: '12442'
file_name: 2022_FrontiersNeuroscience_Weiffert2.pdf
file_size: 19798610
relation: main_file
success: 1
file_date_updated: 2023-01-30T09:15:13Z
has_accepted_license: '1'
intvolume: ' 16'
isi: 1
keyword:
- General Neuroscience
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
publication: Frontiers in Neuroscience
publication_identifier:
issn:
- 1662-453X
publication_status: published
publisher: Frontiers Media
quality_controlled: '1'
scopus_import: '1'
status: public
title: Influence of denaturants on amyloid β42 aggregation kinetics
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 16
year: '2022'
...