title: Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions.
abstract: Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Olzscha
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Schermann
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Woerner
authors.forename: Stefan
authors.initials: S
authors.lastname: Pinkert
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hecht
authors.forename: Gian G
authors.initials: GG
authors.lastname: Tartaglia
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: Manajit
authors.initials: M
authors.lastname: Hayer-Hartl
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
authors.forename: R Martin
authors.initials: RM
authors.lastname: Vabulas
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D002460:Cell Line; D002468:Cell Physiological Phenomena; D006801:Humans; D046912:Multiprotein Complexes; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics
chemical_list: D000682:Amyloid; D046912:Multiprotein Complexes; D011506:Proteins