Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.
Elife
; 62017 11 17.
Article
em En
| MEDLINE
| ID: mdl-29148426
ABSTRACT
Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique ß-strand structure distinct from the conventional amyloid ß-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Multimerização Proteica
/
Polipeptídeo Amiloide das Ilhotas Pancreáticas
/
Agregados Proteicos
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha