Correlations among morphology, beta-sheet stability, and molecular structure in prion peptide aggregates.
The misfolding of proteins into beta-sheets and the subsequent aggregation of these sheets into fibrous networks underlies many diseases. In this paper, the role of peptide structure in determining the ordering of beta-sheet aggregates and the morphology of fibrils and protofibrils is dissected. Using a series of peptides based on residues 109-122 of the Syrian hamster prion protein (H1) with a range of substitutions at position 117, the link between side chain interactions and beta-sheet thermal stability has been investigated. The thermal stability of beta-sheets is associated with the peptides' ability to adopt the same alignment as wild-type H1, with residue 117 in register across all beta-strands [Silva, R. A. G. D., Barber-Armstrong, W., and Decatur, S. M. (2003) J. Am. Chem. Soc. 125, 13674-13675]. These aligned strands are capable of forming long, rigid, and twisted fibrils (as visualized by atomic force microscopy) which are thermostable. Peptides which do not adopt this strand alignment aggregate to form thin, flexible, and smooth protofibrils. The ability to form ordered aggregates, and thus to form twisted fibrils, is modulated by the structure of the side chain of residue 117.
Petty
Sarah A
SA
Department of Chemistry, Mount Holyoke College, 50 College Street, South Hadley, Massachusetts 01075, USA.
Adalsteinsson
Thorsteinn
T
Decatur
Sean M
SM
D000409:Alanine / Q000737:chemistry; D019943:Amino Acid Substitution; D000818:Animals; D002247:Carbon Isotopes / Q000378:metabolism; D006224:Cricetinae; D008647:Mesocricetus; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000648:ultrastructure; D011328:Prions / Q000737:chemistry* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
D002247:Carbon Isotopes; D010446:Peptide Fragments; D011328:Prions; D000409:Alanine