Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs.
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.
Sato
Toru
T
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nyborg
Andrew C
AC
Iwata
Nobuhisa
N
Diehl
Thekla S
TS
Saido
Takaomi C
TC
Golde
Todd E
TE
Wolfe
Michael S
MS
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D002474:Cell-Free System / Q000737:chemistry; D017124:Conserved Sequence; D010450:Endopeptidases / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D011388:Prolactin / Q000737:chemistry
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011388:Prolactin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase; C509280:BACE1 protein, human