title: Domain architecture of the polyglutamine protein ataxin-3: a globular domain followed by a flexible tail.
abstract: Anomalous expansion of a polyglutamine (polyQ) tract in the protein ataxin-3 causes spinocerebellar ataxia type 3, an autosomal dominant neurodegenerative disease. Very little is known about the structure and the function of ataxin-3, although this information would undoubtedly help to understand why the expanded protein forms insoluble nuclear aggregates and causes neuronal cell death. With the aim of establishing the domain architecture of ataxin-3 and the role of the polyQ tract within the protein context, we have studied the human and murine orthologues using a combination of techniques, which range from limited proteolysis to circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopies. The two protein sequences share a highly conserved N-terminus and differ only in the length of the glutamine repeats and in the C-terminus. Our data conclusively indicate that ataxin-3 is composed by a structured N-terminal domain, followed by a flexible tail. Moreover, [(15)N]glutamine selectively labelled samples allowed us to have a direct insight by NMR into the structure of the polyQ region.
authors.affiliation: National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Masino
authors.forename: Valeria
authors.initials: V
authors.lastname: Musi
authors.forename: Rajesh P
authors.initials: RP
authors.lastname: Menon
authors.forename: Paola
authors.initials: P
authors.lastname: Fusi
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Frenkiel
authors.forename: Yvon
authors.initials: Y
authors.lastname: Trottier
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000067699:Ataxin-3; D002942:Circular Dichroism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009587:Nitrogen Isotopes; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D016415:Sequence Alignment; D014157:Transcription Factors
chemical_list: D009419:Nerve Tissue Proteins; D009587:Nitrogen Isotopes; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C097188:polyglutamine; D010447:Peptide Hydrolases; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse