PUBLICATION

Signal Peptide Peptidases and Gamma-Secretase: Cousins of the Same Protease Family?

Authors
Fluhrer, R., and Haass, C.
ID
ZDB-PUB-070711-10
Date
2007
Source
Neuro-degenerative Diseases   4(2-3): 112-116 (Review)
Registered Authors
Haass, Christian
Keywords
Alzheimer's disease, Presenilin, Signal peptide peptidase, GxGD proteases, Regulated intramembrane cleavage
MeSH Terms
  • Amyloid Precursor Protein Secretases*
  • Animals
  • Aspartic Acid Endopeptidases*
  • Endoplasmic Reticulum/enzymology
  • Humans
  • Protein Sorting Signals
PubMed
17596705 Full text @ Neurodegener. Dis.
Abstract
Signal peptide peptidase (SPP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2,and sppl3 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNFalpha intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article, we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others.
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