PUBLICATION

Cellular Functions of gamma-Secretase-Related Proteins

Authors
Haffner, C., and Haass, C.
ID
ZDB-PUB-061020-54
Date
2006
Source
Neuro-degenerative Diseases   3(4-5): 284-289 (Journal)
Registered Authors
Haass, Christian, Haffner, Christof
Keywords
Nodal modulator, Presenilin, Signal peptide peptidase, Nodal signaling pathway, Nicastrin-like protein
MeSH Terms
  • Amyloid Precursor Protein Secretases/chemistry
  • Amyloid Precursor Protein Secretases/metabolism*
  • Animals
  • Aspartic Acid Endopeptidases/metabolism*
  • Humans
  • Membrane Glycoproteins/chemistry
  • Membrane Glycoproteins/metabolism
  • Presenilins/chemistry
  • Presenilins/metabolism
  • Zebrafish/embryology
  • Zebrafish/physiology
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/metabolism
PubMed
17047369 Full text @ Neurodegener. Dis.
Abstract
Amyloid-beta peptide (Abeta) is generated by gamma-secretase, a membrane protein complex with an unusual aspartyl protease activity consisting of the four components presenilin, nicastrin, APH-1 and PEN-2. Presenilin is considered the catalytic subunit of this complex since it represents the prototype of the new family of intramembrane-cleaving GxGD-type aspartyl proteases. Recently, five novel members of this family and a nicastrin-like protein were identified. Whereas one of the GxGD-type proteins was shown to be identical with signal peptide peptidase (SPP), the function of the others, now called SPP-like proteins (SPPLs), is not known. We therefore analyzed SPPL2b and SPPL3 and demonstrated that they localize to different subcellular compartments suggesting nonredundant functions. This was supported by different phenotypes obtained in knockdown studies in zebrafish embryos. In addition, these phenotypes could be phenocopied by ectopic expression of putative active site mutants, providing strong evidence for a proteolytic function of SPPL2b and SPPL3. We also identified and characterized the nicastrin-like protein nicalin which, together with the 130-kDa protein NOMO (Nodal modulator), forms a membrane protein complex different from gamma-secretase. We found that during zebrafish embryogenesis this complex is involved in the patterning of the axial mesendoderm, a process controlled by the Nodal signaling pathway.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping