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.