Determinants of amyloid fibril degradation by the PDZ protease HTRA1

• Published in: Nature chemical biology Vol. 11; no. 11; pp. 862 - 869
• Main Authors: Poepsel, Simon, Sprengel, Andreas, Sacca, Barbara, Kaschani, Farnusch, Kaiser, Markus, Gatsogiannis, Christos, Raunser, Stefan, Clausen, Tim, Ehrmann, Michael
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2015; Nature Publishing Group
• Subjects: 13/106; 631/378/340; 631/45; 631/92/468; 631/92/470; 82/58; 82/83; Amyloid - chemistry; Amyloid - genetics; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; ATP; Biochemical Engineering; Biochemistry; Biodegradation; Biological Transport; Bioorganic Chemistry; Cell Biology; Cellular biology; Chemistry; Chemistry/Food Science; Disease; Gene Expression; HEK293 Cells; High-Temperature Requirement A Serine Peptidase 1; Humans; PDZ Domains; Peptide Fragments - chemistry; Peptide Fragments - genetics; Proteases; Protein Aggregates; Protein Conformation; Proteins; Proteolysis; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Serine Endopeptidases - chemistry; Serine Endopeptidases - genetics; tau Proteins - chemistry; tau Proteins - genetics
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1931

The serine protease HTRA1 utilizes a "disintegration" mechanism involving its flexible PDZ domains to first loosen tau amyloid fibrils and subsequently disintegrating the fibrillar core structure for efficient proteolytic degradation. 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.