Cathepsins S, B and L with aminopeptidases display β-secretase activity associated with the pathogenesis of Alzheimer’s disease
-
Israel Schechter
and Etty Ziv
Abstract
β-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) β-site very slowly (kcat/Km: 46.6 m-1s-1). Therefore we searched for additional β-secretases and identified three cathepsins that split the WT β-site much faster. Human cathepsin S cleaves the WT β-site (kcat/Km: 54 700 m-1s-1) 1170-fold faster than BACE1 and cathepsins B and L are 440- and 74-fold faster than BACE1, respectively. These cathepsins split two bonds flanking the WT β-site (K-MD-A), where the K-M bond (85%) is cleaved more efficiently than the D-A bond (15%). Cleavage at the major K-M bond yields Aβ (amyloid β-peptide) extended by N-terminal Met that should be removed to generate Aβ initiated by Asp1. The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp. Brain aminopeptidases showed similar specificity. Thus, aminopeptidases would convert Aβ extended by Met into regular Aβ (Asp1) found in amyloid plaques. Earlier studies indicate that Aβ is likely produced in the endosome and lysosome system where cathepsins S, B and L are localized and cysteine cathepsin inhibitors reduce the level of Aβ in cells and animals. Taken together, cathepsins S, B and L deserve further evaluation as therapeutic targets to develop disease modifying drugs to treat Alzheimer’s disease.
©2011 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Publisher’s Note
- Publisher’s Note
- GENES AND NUCLEIC ACIDS
- Intermolecular interaction between a branching ribozyme and associated homing endonuclease mRNA
- Type V collagen-induced upregulation of capn2 (large subunit of m-calpain) gene expression and DNA fragmentation in 8701-BC breast cancer cells
- PROTEIN STRUCTURE AND FUNCTION
- High catalytic efficiency and resistance to denaturing in bacterial Rho GTPase-activating proteins
- MEMBRANES, LIPIDS, GLYCOBIOLOGY
- Cloning and functional analysis of the dpm2 and dpm3 genes from Trichoderma reesei expressed in a Saccharomyces cerevisiae dpm1Δ mutant strain
- MOLECULAR MEDICINE
- Increased expression of the multidrug resistance-associated protein 1 (MRP1) in kidney glomeruli of streptozotocin-induced diabetic rats
- CELL BIOLOGY AND SIGNALING
- Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R-/- mice
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- Angiotensin I-converting enzyme (ACE) activity and expression in rat central nervous system after sleep deprivation
- Cathepsins S, B and L with aminopeptidases display β-secretase activity associated with the pathogenesis of Alzheimer’s disease
- The role of cathepsin E in terminal differentiation of keratinocytes
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