title: De novo design of a biologically active amyloid.
abstract: 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.
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Meine
authors.initials: M
authors.lastname: Ramakers
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Claes
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.|Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Ladan
authors.initials: L
authors.lastname: Khodaparast
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.|Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Laleh
authors.initials: L
authors.lastname: Khodaparast
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: José R
authors.initials: JR
authors.lastname: Couceiro
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Tobias
authors.initials: T
authors.lastname: Langenberg
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.|Laboratory of Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Siemons
authors.affiliation: IFM Department of Chemistry, Linköping University, Linköping, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Nyström
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Young
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Romain F
authors.initials: RF
authors.lastname: Laine
authors.affiliation: Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.|School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Young
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.|Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.|Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.affiliation: Stem Cell Institute, KU Leuven, Leuven, Belgium.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: VIB Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Staes
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.|Laboratory of Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Matyas
authors.initials: M
authors.lastname: Desager
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology Research Unit, Endothelial Cell Biology Unit, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Manu
authors.initials: M
authors.lastname: Beerens
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology Research Unit, Endothelial Cell Biology Unit, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Vandervoort
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology Research Unit, Endothelial Cell Biology Unit, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
authors.affiliation: VIB Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Laboratory of Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Van Eldere
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Biomedical MRI Unit/MoSAIC, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Greetje
authors.initials: G
authors.lastname: Vande Velde
authors.affiliation: Stem Cell Institute, KU Leuven, Leuven, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.|Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: IFM Department of Chemistry, Linköping University, Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.affiliation: IFM Department of Chemistry, Linköping University, Linköping, Sweden.
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, East Sussex BN1 9QG, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Serpell
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium. frederic.rousseau@switch.vib-kuleuven.be joost.schymkowitz@switch.vib-kuleuven.be.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: VIB Switch Laboratory, Leuven, Belgium. frederic.rousseau@switch.vib-kuleuven.be joost.schymkowitz@switch.vib-kuleuven.be.|Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven (KU Leuven), Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000686:Amyloidosis / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D066263:Protein Aggregation, Pathological / Q000139:chemically induced / Q000378:metabolism*; D021382:Protein Sorting Signals; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010455:Peptides; D021382:Protein Sorting Signals; C000617175:vascin; D040301:Vascular Endothelial Growth Factor Receptor-2