Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization
The Huntingtin protein (HTT), named for its role in Huntington's disease, has been best understood as a scaffolding protein that promotes vesicle transport by molecular motors along microtubules. Here, we show that HTT also interacts with the actin cytoskeleton, and its loss of function disturbs the morphology and function of the axonal growth cone. We demonstrate that HTT organizes F-actin into bundles. Cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) structural analyses reveal that HTT's N-terminal HEAT and Bridge domains wrap around F-actin, while the C-terminal HEAT domain is displaced; furthermore, HTT dimerizes via the N-HEAT domain to bridge parallel actin filaments separated by ~20 nanometers. Our study provides the structural basis for understanding how HTT interacts with and organizes the actin cytoskeleton.
Authors
- Béatrice Blot (ORCID: https://orcid.org/0000-0002-6279-5764)
- Sandrine Humbert (ORCID: https://orcid.org/0000-0002-9501-2658)
- Éric Denarier (ORCID: https://orcid.org/0000-0002-4169-397X)
- Isabelle Arnal (ORCID: https://orcid.org/0000-0001-6149-8189)
- Ji‐Joon Song (ORCID: https://orcid.org/0000-0001-7120-6311)
- Doory Kim (ORCID: https://orcid.org/0000-0002-2675-106X)
- María J. Marcaida (ORCID: https://orcid.org/0000-0003-0663-5309)
- Hyeongju Kim (ORCID: https://orcid.org/0000-0001-8668-0323)
- Jesse M. Hansen (ORCID: https://orcid.org/0000-0001-7967-2085)
- Matteo Dal Peraro (ORCID: https://orcid.org/0000-0002-2973-3975)
- J. H. Kim (ORCID: https://orcid.org/0000-0002-0695-8549)
- Mariacristina Capizzi (ORCID: https://orcid.org/0000-0001-6601-8439)
- Florian Fäßler (ORCID: https://orcid.org/0000-0001-7149-769X)
- Rémi Carpentier (ORCID: https://orcid.org/0000-0002-3950-7621)
- Marine Degennaro
- F.K.M. Schur (ORCID: https://orcid.org/0000-0003-4790-8078)
- Min Seong Kim (ORCID: https://orcid.org/0009-0005-3087-220X)
- Sophia Labou
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Korea Advanced Institute of Science and Technology (KR)
- Institute of Science and Technology Austria (AT)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Grenoble (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Pitié-Salpêtrière Hospital (FR)
- Grenoble Institute of Neurosciences (FR)
- Institut du Cerveau (FR)
- Hanyang University (KR)
- École Polytechnique Fédérale de Lausanne (CH)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-19
- DOI
- https://doi.org/10.1126/sciadv.adw4124
- Citations
- 6
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 5.45