Related Experiment Video

Updated: Oct 10, 2025

Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy
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Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy

Published on: June 27, 2018

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Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1

Rachel J Harding1, Justin C Deme2,3,4, Johannes F Hevler5,6

  • 1Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. Rachel.Harding@utoronto.ca.

Communications Biology
|December 9, 2021
PubMed

Insights

Huntington's disease research reveals how the huntingtin protein (HTT) interacts with HAP40. This study provides a structural basis for understanding HTT's function and developing new therapies.

Area of Science:

  • Structural Biology
  • Neurodegenerative Diseases
  • Molecular Medicine

Background:

  • Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene.
  • Wild-type and mutant HTT form a stable heterodimer with HAP40.
  • The functional relevance of the HTT-HAP40 interaction is not fully understood.

Purpose of the Study:

  • To elucidate the structural basis of the HTT-HAP40 interaction.
  • To investigate the functional consequences of polyglutamine expansion in HTT.
  • To provide insights for Huntington's disease drug discovery.

Main Methods:

  • Cryo-electron microscopy (2.6 Å resolution)
  • Cross-linking mass spectrometry
  • Small-angle X-ray scattering
  • Native mass spectrometry
  • Computational modeling

Main Results:

  • A near-atomic-level structural model of the HTT-HAP40 complex was determined.
  • HTT and HAP40 cellular abundance is coupled, suggesting interdependence.
  • The HTT-HAP40 heterodimer is highly stable.
  • Polyglutamine expansion in HTT exon 1 increases its conformational flexibility.

Conclusions:

  • The study reveals the structural organization of HTT, orchestrated by HAP40.
  • The findings explain the coupled cellular abundance of HTT and HAP40.
  • This work lays the groundwork for future functional studies and therapeutic strategies for Huntington's disease.

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