title: Length-dependent conformational transitions of polyglutamine repeats as molecular origin of fibril initiation.
abstract: Polyglutamine (polyQ) sequences are found in a variety of proteins with normal function. However, their repeat expansion is associated with a number of neurodegenerative diseases, also called polyQ diseases. The length of the polyQ sequence, varying in the number of consecutive glutamines among different diseases, is critical for inducing fibril formation. We performed a systematic spectroscopic study to analyze the conformation of polyQ model peptides in dependence of the glutamine sequence lengths (K2QnK2 with n=10, 20, 30). Complementary FTIR- and CD-spectra were measured in a wide concentration range and repeated heating and cooling cycles revealed the thermal stability of formed β-sheets. The shortest glutamine sequence K2Q10K2 shows solely random structure for concentrations up to 10 mg/ml. By increasing the peptide length to K2Q20K2, a significant fraction of β-sheet is observed even at low concentrations of 0.01 mg/ml. The higher the concentration, the more the structural composition is dominated by the intermolecular β-sheet. The formation of highly thermostable β-sheet is much more pronounced in K2Q30K2. K2Q30K2 precipitates at a concentration of 0.3 mg/ml. Our spectroscopic study shows that the aggregation tendency is enhanced with increased glutamine repeat expansion and that the concentration plays another critical factor in the β-sheet formation.
authors: Department of Chemistry and Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany.
authors: Benjamin S
authors: BS
authors: Heck
authors: Department of Chemistry and Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany.
authors: Franziska
authors: F
authors: Doll
authors: Department of Chemistry and Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany. Electronic address: Karin.Hauser@uni-konstanz.de.
authors: Karin
authors: K
authors: Hauser
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D010455:Peptides; C097188:polyglutamine
keywords: CD; Conformation; Fibril formation; IR; Peptides; Polyglutamine