Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation.

Date publication

janvier 2015

Journal

The Journal of biological chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MONSELLIER Elodie

Tous les auteurs :
Monsellier E, Redeker V, Ruiz-Arlandis G, Bousset L, Melki R

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/25505179

Résumé

The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ-containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease.

Mots clés

Heat Shock Protein (HSP), Huntington Disease, Mass Spectrometry (MS), Molecular Chaperone, Neurodegenerative Disease, Polyglutamine, Protein Aggregation

Référence

J Biol Chem. 2015 01 30;290(5):2560-76