Processive proteolysis by γ-secretase and the mechanism of Alzheimer’s disease
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Michael S. Wolfe
Abstract
γ-Secretase is a membrane-embedded protease complex with presenilin as the catalytic component. Cleavage within the transmembrane domain of the amyloid β-protein precursor (APP) by γ-secretase produces the C-terminus of the amyloid β-peptide (Aβ), a proteolytic product prone to aggregation and strongly linked to Alzheimer’s disease (AD). Presenilin mutations are associated with early-onset AD, but their pathogenic mechanisms are unclear. One hypothesis is that these mutations cause AD through a toxic gain of function, changing γ-secretase activity to increase the proportion of 42-residue Aβ over the more soluble 40-residue form. A competing hypothesis is that the mutations cause AD through a loss of function, by reducing γ-secretase activity. However, γ-secretase apparently has two types of activities, an endoproteolytic function that first cuts APP to generate a 48/49-residue form of Aβ, and a carboxypeptidase activity that processively trims these longer Aβ intermediates approximately every three residues to form shorter, secreted forms. Recent studies suggest a resolution of the gain-of-function vs. loss-of-function debate: presenilin mutations may increase the proportion of longer, more aggregation-prone Aβ by specifically decreasing the trimming activity of γ-secretase. That is, the reduction of this particular proteolytic function of presenilin, not its endoproteolytic activity, may lead to the neurotoxic gain of function.
©2012 by Walter de Gruyter Berlin Boston
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Artikel in diesem Heft
- Masthead
- Masthead
- Guest Editorial
- Highlight: The universe of proteolytic networks and mechanisms
- Highlight: 7th General Meeting of the International Proteolysis Society
- Current and prospective applications of non-proteinogenic amino acids in profiling of proteases substrate specificity
- Understanding the substrate specificity of conventional calpains
- Protease-dependent mechanisms of complement evasion by bacterial pathogens
- An ensemble view of thrombin allostery
- Processive proteolysis by γ-secretase and the mechanism of Alzheimer’s disease
- TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections
- A catalogue of putative HIV-1 protease host cell substrates
- Identifi cation of protease exosite-interacting peptides that enhance substrate cleavage kinetics
- A plant Kunitz-type inhibitor mimics bradykinin-induced cytosolic calcium increase and intestinal smooth muscle contraction
- Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice
- Disruption of gingipain oligomerization into non-covalent cell-surface attached complexes
- Review
- Synthesis and biological actions of diphosphoinositol phosphates (inositol pyrophosphates), regulators of cell homeostasis
- Minireviews
- Redox Biology on the rise
- Adipose triglyceride lipase in immune response, inflammation, and atherosclerosis
- Research Articles/Short Communications
- Protein Structure and Function
- Insights into the modulation of optimum pH by a single histidine residue in arginine deiminase from Pseudomonas aeruginosa
