title: Determinants of amyloid fibril degradation by the PDZ protease HTRA1.
abstract: Excessive aggregation of proteins has a major impact on cell fate and is a hallmark of amyloid diseases in humans. To resolve insoluble deposits and to maintain protein homeostasis, all cells use dedicated protein disaggregation, protein folding and protein degradation factors. Despite intense recent research, the underlying mechanisms controlling this key metabolic event are not well understood. Here, we analyzed how a single factor, the highly conserved serine protease HTRA1, degrades amyloid fibrils in an ATP-independent manner. This PDZ protease solubilizes protein fibrils and disintegrates the fibrillar core structure, allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. The aggregate burden in a cellular model of cytoplasmic tau aggregation is thus reduced. Mechanistic aspects of ATP-independent proteolysis and its implications in amyloid diseases are discussed.
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Poepsel
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sprengel
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sacca
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Farnusch
authors.initials: F
authors.lastname: Kaschani
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Department of Structural Biochemistry, Max Planck Institute Molecular Physiology, Dortmund, Germany.
authors.forename: Christos
authors.initials: C
authors.lastname: Gatsogiannis
authors.affiliation: Department of Structural Biochemistry, Max Planck Institute Molecular Physiology, Dortmund, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Raunser
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Tim
authors.initials: T
authors.lastname: Clausen
authors.affiliation: Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.|School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D001692:Biological Transport; D015870:Gene Expression; D057809:HEK293 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D054731:PDZ Domains; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D066329:Protein Aggregates; D011487:Protein Conformation; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D010446:Peptide Fragments; D066329:Protein Aggregates; D011993:Recombinant Fusion Proteins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases