Identification of the multicatalytic enzyme as a possible gamma-secretase for the amyloid precursor protein.
One of the main components of the senile plaques in brain tissue from patients with Alzheimer's disease is the beta-amyloid peptide. This peptide is proteolytically cleaved from the amyloid precursor protein by the action of at least two proteases, a beta-secretase which generates the N-terminus and a gamma-secretase which generates the C-terminus. Neither of these proteases have been identified. To identify proteases that are candidates for the gamma-secretase we synthesized a small fluorescent peptide substrate containing the amino acids comprising the C-terminus of the longest beta-amyloid peptide identified. This substrate is hydrolyzed by a single activity in homogenates from both cells and brain tissue and we have demonstrated that this activity is the multicatalytic enzyme or proteasome. Furthermore, using specific inhibitors, we have demonstrated that the fluorescent substrate is hydrolyzed by the chymotrypsin-like activity of the multicatalytic enzyme.
Mundy
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DI
Department of Neurology, Baylor College of Medicine, Houston, TX 77030.
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism; D016716:PC12 Cells; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex