title: Natural tri- to hexapeptides self-assemble in water to amyloid beta-type fiber aggregates by unexpected alpha-helical intermediate structures.
abstract: Many fatal neurodegenerative diseases such as Alzheimer's, Parkinson, the prion-related diseases, and non-neurodegenerative disorders such as type II diabetes are characterized by abnormal amyloid fiber aggregates, suggesting a common mechanism of pathogenesis. We have discovered that a class of systematically designed natural tri- to hexapeptides with a characteristic sequential motif can simulate the process of fiber assembly and further condensation to amyloid fibrils, probably via unexpected dimeric α-helical intermediate structures. The characteristic sequence motif of the novel peptide class consists of an aliphatic amino acid tail of decreasing hydrophobicity capped by a polar head. To our knowledge, the investigated aliphatic tripeptides are the shortest ever reported naturally occurring amino acid sequence that can adopt α-helical structure and promote amyloid formation. We propose the stepwise assembly process to be associated with characteristic conformational changes from random coil to α-helical intermediates terminating in cross-β peptide structures. Circular dichroism and X-ray fiber diffraction analyses confirmed the concentration-dependent conformational changes of the peptides in water. Molecular dynamics simulating peptide behavior in water revealed monomer antiparallel pairing to dimer structures by complementary structural alignment that further aggregated and stably condensed into coiled fibers. The ultrasmall size and the dynamic facile assembly process make this novel peptide class an excellent model system for studying the mechanism of amyloidogenesis, its evolution and pathogenicity. The ability to modify the properties of the assembled structures under defined conditions will shed light on strategies to manipulate the pathogenic amyloid aggregates in order to prevent or control aggregate formation.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669. chauser@ibn.a-star.edu.sg
authors.forename: Charlotte A E
authors.initials: CA
authors.lastname: Hauser
authors.forename: Rensheng
authors.initials: R
authors.lastname: Deng
authors.forename: Archana
authors.initials: A
authors.lastname: Mishra
authors.forename: Yihua
authors.initials: Y
authors.lastname: Loo
authors.forename: Ulung
authors.initials: U
authors.lastname: Khoe
authors.forename: Furen
authors.initials: F
authors.lastname: Zhuang
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cheong
authors.forename: Angelo
authors.initials: A
authors.lastname: Accardo
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sullivan
authors.forename: Christian
authors.initials: C
authors.lastname: Riekel
authors.forename: Jackie Y
authors.initials: JY
authors.lastname: Ying
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Hauser
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D002942:Circular Dichroism; D057927:Hydrophobic and Hydrophilic Interactions; D008855:Microscopy, Electron, Scanning; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D014867:Water / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D014867:Water