Role for the alpha-helix in aberrant protein aggregation.
Is the alpha-helix structure capable of triggering the formation of aberrant protein aggregates? To answer this question, we investigate the in vitro aggregation of tau protein in the presence of the helix-inducing agent TFE. Tau is a natively unfolded protein that binds to microtubules and forms aggregates in Alzheimer's disease. We find that full-length tau has residual alpha-helix structure, which is further enhanced by three mutations involved in genetic neurological disorders. TFE concentrations matching an alpha-helical content of 40% in full-length tau and the triple mutant induce the formation of aggregates that are morphologically and structurally heterogeneous. A simple dilution experiment reveals that heterogeneity results from the competition between alpha-helical fibrillar aggregates and more classical amyloid-like aggregates. The alpha-helical aggregates are more resilient to dilution and have the spectroscopic features of alpha-helical coiled coils. We propose a general mechanism by which intrinsically stable alpha-helices can associate into aggregates with only coarse coiled-coil symmetry. In tau, high intrinsic alpha-helix stability and coarse coiled-coil symmetry could be byproducts of its biological function.
Kunjithapatham
Rani
R
Department of Chemistry and Biochemistry and Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland 20742, USA.
Oliva
Fabiana Y
FY
Doshi
Urmi
U
Pérez
Mar
M
Avila
Jesus
J
Muñoz
Victor
V
D001665:Binding Sites; D002942:Circular Dichroism; D006801:Humans; D018625:Microscopy, Atomic Force; D011138:Polytetrafluoroethylene; D011487:Protein Conformation; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure
D011506:Proteins; D016875:tau Proteins; D011138:Polytetrafluoroethylene