Flanking regions, amyloid cores, and polymorphism: the potential interplay underlying structural diversity.
J Biol Chem
; 299(9): 105122, 2023 09.
Article
em En
| MEDLINE
| ID: mdl-37536631
ABSTRACT
The ß-sheet-rich amyloid core is the defining feature of protein aggregates associated with neurodegenerative disorders. Recent investigations have revealed that there exist multiple examples of the same protein, with the same sequence, forming a variety of amyloid cores with distinct structural characteristics. These structural variants, termed as polymorphs, are hypothesized to influence the pathological profile and the progression of different neurodegenerative diseases, giving rise to unique phenotypic differences. Thus, identifying the origin and properties of these structural variants remain a focus of studies, as a preliminary step in the development of therapeutic strategies. Here, we review the potential role of the flanking regions of amyloid cores in inducing polymorphism. These regions, adjacent to the amyloid cores, show a preponderance for being structurally disordered, imbuing them with functional promiscuity. The dynamic nature of the flanking regions can then manifest in the form of conformational polymorphism of the aggregates. We take a closer look at the sequences flanking the amyloid cores, followed by a review of the polymorphic aggregates of the well-characterized proteins amyloid-ß, α-synuclein, Tau, and TDP-43. We also consider different factors that can potentially influence aggregate structure and how these regions can be viewed as novel targets for therapeutic strategies by utilizing their unique structural properties.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Amiloide
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos