Determinants of amyloid fibril degradation by the PDZ protease HTRA1

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry*
  • Amyloid / genetics
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Biological Transport
  • Gene Expression
  • HEK293 Cells
  • High-Temperature Requirement A Serine Peptidase 1
  • Humans
  • PDZ Domains
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Protein Aggregates
  • Protein Conformation
  • Proteolysis
  • Recombinant Fusion Proteins / chemistry*
  • Recombinant Fusion Proteins / genetics
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / genetics
  • tau Proteins / chemistry*
  • tau Proteins / genetics

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • MAPT protein, human
  • Peptide Fragments
  • Protein Aggregates
  • Recombinant Fusion Proteins
  • amyloid beta-protein (1-42)
  • tau Proteins
  • High-Temperature Requirement A Serine Peptidase 1
  • HtrA1 protein, human
  • Serine Endopeptidases