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

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 resulting assemblies. Significance: We identify the surface interfaces between Hsc70 and huntingtin exon 1, which allows the design of future therapeutic tools. 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.

• Publication year

  2014

• Venue

  Journal of Biological Chemistry

• Publication date

  2014-12-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M114.603332PMID 25505179PMCID PMC4317008
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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