Suppression of aggregate and amyloid formation by a novel intrinsically disordered region in metazoan Hsp110 chaperones.
J Biol Chem
; 296: 100567, 2021.
Article
em En
| MEDLINE
| ID: mdl-33753171
ABSTRACT
Molecular chaperones maintain proteostasis by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to numerous neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's disease. Hsp110 is related to the canonical Hsp70 class of protein-folding molecular chaperones and interacts with Hsp70 as a nucleotide exchange factor (NEF). In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate-binding domain (SBD) whose biological roles remain undefined. Previous work in Drosophila melanogaster has implicated the sole Hsp110 gene (Hsc70cb) in proteinopathic neurodegeneration. We hypothesize that in addition to its role as an Hsp70 NEF, Drosophila Hsp110 may function as a protective protein "holdase," preventing the aggregation of unfolded polypeptides via the SBD-ß subdomain. We demonstrate for the first time that Drosophila Hsp110 effectively prevents aggregation of the model substrate citrate synthase. We also report the discovery of a redundant and heretofore unknown potent holdase capacity in a 138-amino-acid region of Hsp110 carboxyl terminal to both SBD-ß and SBD-α (henceforth called the C-terminal extension). This sequence is highly conserved in metazoan Hsp110 genes, completely absent from fungal representatives, and is computationally predicted to contain an intrinsically disordered region (IDR). We demonstrate that this IDR sequence within the human Hsp110s, Apg-1 and Hsp105α, inhibits the formation of amyloid Aß-42 and α-synuclein fibrils in vitro but cannot mediate fibril disassembly. Together these findings establish capacity for metazoan Hsp110 chaperones to suppress both general protein aggregation and amyloidogenesis, raising the possibility of exploitation of this IDR for therapeutic benefit.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article