title: Expansion of amino acid homo-sequences in proteins: insights into the role of amino acid homo-polymers and of the protein context in aggregation.
abstract: Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins, chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology.
authors.affiliation: National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: R P
authors.initials: RP
authors.lastname: Menon
authors.forename: A
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000596:Amino Acids / Q000502:physiology*; D000818:Animals; D000067699:Ataxin-3; D001704:Biopolymers / Q000737:chemistry; D019556:COS Cells; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000235:genetics; D016368:Frameshift Mutation; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000737:chemistry*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014162:Transfection; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: D000596:Amino Acids; D001704:Biopolymers; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3