title: The impact of ataxin-1-like histidine insertions on polyglutamine aggregation.
abstract: Spinocerebellar ataxia type 1 (SCA1) is one of a group of nine expanded CAG repeat diseases, in which polyglutamine (polyQ) expansion above a threshold is associated with increased disease risk and aggregation. SCA1 is unique in which the polyQ in the disease protein, ataxin1, often contains a few His residues that appear to block toxicity. Here, we ask how His insertions affect aggregation by comparing a Q(30) peptide with and without a centrally inserted His-Gln-His sequence. We found that at pH 7.5-8.5, His interruptions decrease polyQ aggregation rates but do not change the spontaneous growth mechanism: nucleated growth polymerization with a critical nucleus of one without non-fibrillar intermediates. The decreased aggregation rates are because of reductions in nucleation equilibrium constants. At pH 6, however, the His-interrupted peptide aggregates by a different mechanism that involves a low ThT-binding intermediate and produces a polymorphic amyloid product. In aggregates grown at pH 7.5, the His residues are solvent-accessible. Aggregates of His-inserted polyQ are good seeds for Q(30) elongation, suggesting the potential to recruit polyQ proteins in the cell. Our data are therefore most consistent with His insertions blocking toxicity by suppressing rates and/or altering pathways of spontaneous aggregation.
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Biomedical Sciences Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
mesh_terms: D000067696:Ataxin-1; D000067528:Ataxins; D006639:Histidine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D006639:Histidine