Expansion of amino acid homo-sequences in proteins: insights into the role of amino acid homo-polymers and of the protein context in aggregation

Cell Mol Life Sci. 2006 Jul;63(14):1677-85. doi: 10.1007/s00018-006-6097-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / physiology*
  • Animals
  • Ataxin-3
  • Biopolymers / chemistry
  • COS Cells
  • Chlorocebus aethiops
  • DNA, Complementary / genetics
  • Frameshift Mutation
  • Humans
  • Machado-Joseph Disease / genetics
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Peptides / chemistry*
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry
  • Repetitive Sequences, Amino Acid*
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Sequence Deletion
  • Structure-Activity Relationship
  • Transfection
  • Trinucleotide Repeat Expansion*
  • Trinucleotide Repeats*

Substances

  • Amino Acids
  • Biopolymers
  • DNA, Complementary
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3