De novo design of a biologically active amyloid

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Gallardo, R 
Ramakers, M 
De Smet, F 
Claes, F 
Khodaparast, L 

Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional—determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

Amino Acid Sequence, Amyloid, Amyloidosis, Animals, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Signaling Peptides and Proteins, Mice, Peptide Fragments, Peptides, Protein Aggregation, Pathological, Protein Sorting Signals, Vascular Endothelial Growth Factor Receptor-2
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American Association for the Advancement of Science
Engineering and Physical Sciences Research Council (EP/H018301/1)
Medical Research Council (MC_G1000734)
Medical Research Council (MR/K015850/1)
Medical Research Council (MR/K02292X/1)
This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Framework Programme, ERC grant agreement 647458 (MANGO) to J.S. The Switch Laboratory was supported by grants from VIB, Industrial Research Funds of KU Leuven (IOF), the Funds for Scientific Research Flanders (FWO), the Flanders Institute for Science and Technology (IWT), and the Federal Office for Scientific Affairs of Belgium (Belspo), IUAP P7/16. G.V.V., F.D.S., and F.C. were supported by postdoctoral fellowships of FWO. G.V.V. was also supported by KU Leuven competitive funding (PF/10/014). L.Y. is funded by a Wellcome Trust Institutional Strategic Support Fund (ISSF) (grant 015615/Z/14/Z). The Synapt high-definition mass spectroscopy mass spectrometer was purchased with funds from the Biotechnology and Biological Sciences Research Council through its Research Equipment Initiative scheme (BB/E012558/1). The Linköping University laboratories were supported by The Göran Gustafsson Foundation, The Swedish Research Council, and The Swedish Alzheimer Foundation. P.C. was supported by FWO, Methusalem funding by the Flemish government, and an AXA Research grant. M.K. is supported by a Marie Skłodowska-Curie Individual Fellowship under the European Union’s Horizon 2020 Framework Programme (grant H2020-MSCA-IF-2014-ST). C.V. was supported by the KU Leuven Stem Cell Programme. F.R. and J.S. are inventors on patent applications WO2007/071789 and WO2012/123419 submitted by VIB vzw, Belgium, that covers the use of targeted protein aggregation for therapeutic or biotechnological applications.