The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation.
Amyloid-beta peptide (A beta) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts beta-strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a beta-strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous A beta peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A beta N-terminal domain to adopt an alpha-helical structure, with a concomitant increase in amyloid formation. We propose that A beta exists in an equilibrium between two species: one "able" and another "unable" to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the A beta secondary structure with therapeutical compounds that promote the alpha-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients.
Soto
C
C
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
Castaño
E M
EM
Frangione
B
B
Inestrosa
N C
NC
D000409:Alanine; D000682:Amyloid / Q000096:biosynthesis* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D007202:Indicators and Reagents; D008854:Microscopy, Electron; D008961:Models, Structural; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D014633:Valine
D000682:Amyloid; D016229:Amyloid beta-Peptides; D007202:Indicators and Reagents; D010446:Peptide Fragments; D010455:Peptides; D014633:Valine; D000409:Alanine