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

Journal article

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.

Authors: Harding, RJ; Deme, JC; Hevler, JF; Tamara, S; Lemak, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Biology
• Volume: 4
• Issue: 1
• Pages: 1374-1374
• Article number: 1374
• Publication date: 2021-12-08
• DOI: 10.1038/s42003-021-02895-4
• EISSN: 2399-3642
• ISSN: 2399-3642
• Language: English
• Keywords: Huntingtin Protein; Trinucleotide repeat expansion; Biophysics; Wild type; Biology; Exon; Polyglutamine tract; Cell biology; Mutant; Allele; Chemistry; Dimer; Gene; Genetics; Huntingtin