title: Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function.
abstract: The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vijayvargia
authors.affiliation: Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.
authors.forename: Raquel
authors.initials: R
authors.lastname: Epand
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Leitner
authors.affiliation: Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.|Department of Biosciences and Nutrition, Karolinska Institute, Solna, Sweden.|School of Technology and Health, KTH Royal Institute of Technology, Novum, Sweden.
authors.forename: Tae-Yang
authors.initials: TY
authors.lastname: Jung
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Baehyun
authors.initials: B
authors.lastname: Shin
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Roy
authors.initials: R
authors.lastname: Jung
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lloret
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Randy
authors.initials: R
authors.lastname: Singh Atwal
authors.affiliation: Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Hyeongseok
authors.initials: H
authors.lastname: Lee
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Zurich, Switzerland.|Faculty of Science, University of Zurich, Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institute, Solna, Sweden.|School of Technology and Health, KTH Royal Institute of Technology, Novum, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Hebert
authors.affiliation: Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Ji-Joon
authors.initials: JJ
authors.lastname: Song
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.
authors.forename: Ihn Sik
authors.identifier: http://orcid.org/0000-0003-4246-3356
authors.initials: IS
authors.lastname: Seong
mesh_terms: D055592:Biophysical Phenomena; D002942:Circular Dichroism; D000071058:Huntingtin Protein / Q000737:chemistry* / Q000378:metabolism*; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D010455:Peptides; C097188:polyglutamine
keywords: HEAT/HEAT-like repeat; Huntington's disease; biophysics; neurodegenerative disorders; neuroscience; none; solenoid scaffold protein; structural biology