title: Effect of introducing a short amyloidogenic sequence from the Aβ peptide at the N-terminus of 18-residue amphipathic helical peptides.
abstract: Fibril formation is the hallmark of pathogenesis in Alzheimer's disease and other amyloid disorders caused by conformational alterations leading to the aggregation of soluble monomers. Aβ40 self-associates to form amyloid fibrils. Its central seven-residue segment KLVFFAE (Aβ16-22), which is thought to be crucial for fibril formation of the full-length peptide, forms fibrils even in isolation. Context-dependent induction of amyloid formation by such sequences in peptides, which otherwise do not have that propensity, is of considerable interest. We have examined the effect of introducing the Aβ16-22 sequence at the N-terminus of two amphipathic helical 18-residue peptides Ac-WYSEMKRNVQRLERAIEE-am and Ac-KQLIRFLKRLDRNLWGLA-am, which have high average hydrophobic moment <μH> values but have net charges of 0 and +4, respectively, at neutral pH. Upon incubation in aqueous buffer, fibril-like aggregates were discernible by transmission electron microscopy for the peptide with only 0 net charge, which also displayed ThT binding and β-structure. Although both the sequences have been derived from amphipathic helical segments in globular proteins and possess high average hydrophobic moments, the +4 charge peptide lacks the ability to form fibrils, while the peptide with 0 charge has the tendency to form fibrillar structures. Variation in the net charge and the presence of several glutamic acids in the sequence of the peptide with net charge 0 appear to favor the formation of fibrils when the Aβ16-22 sequence is attached at the N-terminus.
authors: CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
authors: Chandrasekaran
authors: C
authors: SivakamaSundari
authors: Sridharan
authors: S
authors: Rukmani
authors: Ramakrishnan
authors: R
authors: Nagaraj
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013499:Surface Properties; D014269:Trifluoroacetic Acid / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014269:Trifluoroacetic Acid