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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 J. R.; Lea, Susan M.; Arrowsmith, Cheryl H.

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

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  • Media type: E-Article
  • Title: Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1
  • Contributor: 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 J. R.; Lea, Susan M.; Arrowsmith, Cheryl H.
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: Communications Biology
  • Language: English
  • DOI: 10.1038/s42003-021-02895-4
  • ISSN: 2399-3642
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Huntington’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.</jats:p>
  • Access State: Open Access