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

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  • AbstractHuntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo and in cell models that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease and illuminate the structural consequences of HTT polyglutamine expansion.


  • Harding, Rachel J
  • Deme, Justin C
  • Hevler, Johannes F
  • Tamara, Sem
  • Lemak, Alexander
  • Cantle, Jeffrey P
  • Szewczyk, Magdalena M
  • Begeja, Nola
  • Goss, Siobhan
  • Zuo, Xiaobing
  • Loppnau, Peter
  • Seitova, Alma
  • Hutchinson, Ashley
  • Fan, Lixin
  • Truant, Ray
  • Schapira, Matthieu
  • Carroll, Jeffrey B
  • Heck, Albert JR
  • Lea, Susan M
  • Arrowsmith, Cheryl H

publication date

  • December 8, 2021