Liquid-liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation.
IAPP
aggregation
hydrogelation
insulin
liquid–liquid phase separation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
02 06 2020
02 06 2020
Historique:
pubmed:
18
5
2020
medline:
18
8
2020
entrez:
17
5
2020
Statut:
ppublish
Résumé
Amyloidoses (misfolded polypeptide accumulation) are among the most debilitating diseases our aging societies face. Amyloidogenesis can be catalyzed by hydrophobic-hydrophilic interfaces (e.g., air-water interface in vitro [AWI]). We recently demonstrated hydrogelation of the amyloidogenic type II diabetes-associated islet amyloid polypeptide (IAPP), a hydrophobic-hydrophilic interface-dependent process with complex kinetics. We demonstrate that human IAPP undergoes AWI-catalyzed liquid-liquid phase separation (LLPS), which initiates hydrogelation and aggregation. Insulin modulates these processes but does not prevent them. Using nonamyloidogenic rat IAPP, we show that, whereas LLPS does not require the amyloidogenic sequence, hydrogelation and aggregation do. Interestingly, both insulin and rat sequence delayed IAPP LLPS, which may reflect physiology. By developing an experimental setup and analysis tools, we show that, within the whole system (beyond the droplet stage), macroscopic interconnected aggregate clusters form, grow, fuse, and evolve via internal rearrangement, leading to overall hydrogelation. As the AWI-adsorbed gelled layer matures, its microviscosity increases. LLPS-driven aggregation may be a common amyloid feature and integral to pathology.
Identifiants
pubmed: 32414928
pii: 1916716117
doi: 10.1073/pnas.1916716117
pmc: PMC7275713
doi:
Substances chimiques
Amyloid
0
Amyloidogenic Proteins
0
Hydrogels
0
Insulin
0
Islet Amyloid Polypeptide
0
Protein Aggregates
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12050-12061Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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