Signal Peptide Peptidase: Biochemical Properties and Modulation by Nonsteroidal Antiinflammatory Drugs.
From: Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochemistry
- Publish Date: Jul 2006
- ISSN: 0006-2960
- Volume: 45
- Issue: 28
- Pages: 8649-56
- Medium: Print
- Language: English
- Citation (JAMA): Sato Toru, Nyborg Andrew C, Iwata Nobuhisa, et al. Signal Peptide Peptidase: Biochemical Properties and Modulation by Nonsteroidal Antiinflammatory Drugs.. Biochemistry Jul 2006;45:8649-56
Abstract
Signal peptide peptidase (SPP) is an intramembrane aspartyl protease that cleaves remnant signal peptides after their release by signal peptidase. SPP contains active site motifs also found in presenilin, the catalytic component of the gamma-secretase complex of Alzheimer’s disease. However, SPP has a membrane topology opposite that of presenilin, cleaves transmembrane substrates of opposite directionality, and does not require complexation with other proteins. Here we show that, upon isolation of membranes and solubilization with detergent, the biochemical characteristics of SPP are remarkably similar to gamma-secretase. The majority of the SPP-catalyzed cleavages occurred at a single site in a synthetic substrate based on the prolactin (Prl) signal sequence. However, as seen with cleavage of substrates by gamma-secretase, additional cuts at other minor sites are also observed. Like gamma-secretase, SPP is inhibited by helical peptidomimetics and apparently contains a substrate-binding site that is distinct from the active site. Surprisingly, certain nonsteroidal antiinflammatory drugs known to shift the site of proteolysis by gamma-secretase also alter the cleavage site of Prl by SPP. Together, these findings suggest that SPP and presenilin share certain biochemical properties, including a conserved drug-binding site for allosteric modulation of substrate proteolysis.
Mesh Headings (Keywords): Amino Acid Sequence, Amyloid Precursor Protein Secretases, Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspartic Endopeptidases, Binding Sites, Cell Line, Cell-Free System, Conserved Sequence, Endopeptidases, Humans, Molecular Sequence Data, Prolactin
Check for Full Text / PubMed Unique Identifier (PMID): 16834339
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