Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

作者：Élodie Monsellier, Virginie Redeker, Gemma Ruiz-Arlandis, Luc Bousset, Ronald Melki · 发表于：Journal of Biological Chemistry · 年份：2014 · DOI：10.1074/jbc.m114.603332 · 被引用次数：88 · 研究领域：Genetic Neurodegenerative Diseases、Muscle Physiology and Disorders、Mitochondrial Function and Pathology

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. Background: Hsc70 has an alleviating effect on the toxicity of polyglutamine (polyQ)-containing proteins in vivo . Results: Hsc70 binds specifically the N-terminal flank of huntingtin exon 1. Conclusion: Hsc70 interaction with huntingtin exon 1 N-terminal flank affects the conformation of the resu...