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Determinants of amyloid fibril degradation by the PDZ protease HTRA1

Poepsel, Simon, Sprengel, Andreas, Sacca, Barbara, Kaschani, Farnusch, Kaiser, Markus, Gatsogiannis, Christos, Raunser, Stefan, Clausen, Tim and Ehrmann, Michael 2015. Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nature Chemical Biology 11 (11) , pp. 862-869. 10.1038/nchembio.1931

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/1552-4450/ (accessed 11.02.16).
Publisher: Nature Publishing Group
ISSN: 1552-4450
Date of Acceptance: 9 September 2015
Last Modified: 29 Jun 2019 03:14
URI: http://orca.cf.ac.uk/id/eprint/83518

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