title: Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation.
abstract: Polyglutamine (polyGln) expansions in nine human proteins result in neurological diseases and induce the proteins' tendency to form β-rich amyloid fibrils and intracellular deposits. Less well known are at least nine other human diseases caused by polyalanine (polyAla)-expansion mutations in different proteins. The mechanisms of how polyAla aggregates under physiological conditions remain unclear and controversial. We show here that aggregation of polyAla is mechanistically dissimilar to that of polyGln and hence does not exhibit amyloid kinetics. PolyAla assembled spontaneously into α-helical clusters with diverse oligomeric states. Such clustering was pervasive in cells irrespective of visible aggregate formation, and it disrupted the normal physiological oligomeric state of two human proteins natively containing polyAla: ARX and SOX3. This self-assembly pattern indicates that polyAla expansions chronically disrupt protein behavior by imposing a deranged oligomeric status.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Saskia
authors.initials: S
authors.lastname: Polling
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Angelique R
authors.initials: AR
authors.lastname: Ormsby
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Wood
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Kristie
authors.initials: K
authors.lastname: Lee
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: James N
authors.initials: JN
authors.lastname: Hughes
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Michael D W
authors.initials: MD
authors.lastname: Griffin
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: Single Molecule Science and Department of Anatomy, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Quill
authors.initials: Q
authors.lastname: Bowden
authors.affiliation: Single Molecule Science and Department of Anatomy, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Australia.
authors.forename: Till
authors.initials: T
authors.lastname: Böcking
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Australia.
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D010455:Peptides; C019529:polyalanine