De novo design of a biologically active amyloid

Rodrigo Gallardo, Meine Ramakers, Frederik De Smet, Filip Claes, Ladan Khodaparast, Laleh Khodaparast, José R. Couceiro, Tobias Langenberg, Maxime Siemons, Sofie Nyström, Laurence J. Young, Romain F. Laine, Lydia Young, Enrico Radaelli, Iryna Benilova, Manoj Kumar, An Staes, Matyas Desager, Manu Beerens, Petra Vandervoort, Aernout Luttun, Kris Gevaert, Guy Bormans, Mieke Dewerchin, Johan Van Eldere, Peter Carmeliet, Greetje Vande Velde, Catherine Verfaillie, Clemens F. Kaminski, Bart De Strooper, Per Hammarström, K. Peter R. Nilsson, Louise Serpell, Joost Schymkowitz, Frederic Rousseau (see publication in Journal )

Abstract

Amyloid aggregation is driven by short sequences within proteins that self-assemble into characteristic amyloid structures. About 30 human proteins are implicated in amyloid-associated diseases, but many more contain short sequences that are potentially amyloidogenic. Gallardo et al. designed a peptide based on an amyloidogenic sequence in the vascular endothelial growth factor receptor VEGFR2. The peptide induced VEGFR2 to form aggregates with features characteristic of amyloids. Amyloids were toxic only in cells that required VEGFR2 activity, suggesting that the toxicity was due to loss of function of VEGFR2, rather than to inherent toxicity of the aggregates. The peptide inhibited VEGFR2-dependent tumor growth in a mouse tumor model.