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

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

doi:10.1038/s42003-021-02895-4

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

Journal Article · Wed Dec 08 00:00:00 EST 2021 · Communications Biology

DOI:https://doi.org/10.1038/s42003-021-02895-4· OSTI ID:1868916

^[1]; ^[2]; Hevler, Johannes F. ^[3]; ^[3]; Lemak, Alexander ^[1]; Cantle, Jeffrey P. ^[4]; Szewczyk, Magdalena M. ^[1]; Begeja, Nola ^[5]; Goss, Siobhan ^[5]; ^[6]; Loppnau, Peter ^[1]; Seitova, Alma ^[1]; Hutchinson, Ashley ^[1]; Fan, Lixin ^[7]; Truant, Ray ^[5]; ^[1]; Carroll, Jeffrey B. ^[4]; ^[3]; ^[2]; ^[1]

Univ. of Toronto, ON (Canada)
Univ. of Oxford (United Kingdom); National Cancer Institute, Frederick, MD (United States)
Utrecht University (Netherlands); Netherlands Proteomics Center, Utrecht (Netherlands)
Western Washington University, Bellingham, WA (United States)
McMaster Univ., Hamilton, ON (Canada)
Argonne National Lab. (ANL), Argonne, IL (United States)
National Institutes of Health, Frederick, MD (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: European Union; National Institute of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); Wellcome Trust

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1868916

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 4; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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