Alpha-helix structure in Alzheimer's disease aggregates of tau-protein.
The discovery of beta-sheet structure in Alzheimer's amyloid fibrils, and then in many other disease-related protein fibrils, has led to the widely believed view that beta-sheet formation is the general mechanism of aberrant protein aggregation leading to disease. This notion is further reinforced by recent findings, which indicate that normal proteins can be induced to form beta-sheet fibrils in vitro. Alzheimer's disease, a paradigm proteopathy, is accompanied by the formation of two distinct aggregates, amyloid fibrils and paired helical filaments (PHFs). Electron microscope images of PHFs show pairs of twisted ribbons with 80 nm periodicity. However, there is little information of the molecular structure of PHFs, as previous studies have failed to identify signs of regular structure. Using far-UV circular dichroism and Fourier-transformed infrared spectroscopy, we find that PHFs are comprised of alpha-helices. This is remarkable as tau-protein, PHF's primary constituent, has a high abundance of helix-breaking amino acids and is unstructured in solution. We also find that PHFs are very stable, as judged by their high melting temperature and resistance to protease digestion. PHFs are the first example of pathological aggregation associated to the formation of alpha-helix.
Sadqi
Mourad
M
Department of Chemistry and Biochemistry and Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland 20742, USA.
Hernández
Felix
F
Pan
UnMei
U
Pérez
Mar
M
Schaeberle
Michael D
MD
Avila
Jesús
J
Muñoz
Victor
V
D000544:Alzheimer Disease / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D008854:Microscopy, Electron / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D016875:tau Proteins