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Nat Chem Biol. 2015 Nov;11(11):862-9. doi: 10.1038/nchembio.1931. Epub 2015 Oct 5.

Determinants of amyloid fibril degradation by the PDZ protease HTRA1.

Author information

1
Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany.
2
Department of Structural Biochemistry, Max Planck Institute Molecular Physiology, Dortmund, Germany.
3
Research Institute of Molecular Pathology, Vienna, Austria.
4
School of Biosciences, Cardiff University, Cardiff, UK.

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.

PMID:
26436840
DOI:
10.1038/nchembio.1931
[Indexed for MEDLINE]

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