Cellular functions of gamma-secretase-related proteins

Amyloid-beta pepticle (A beta) 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 pepticle 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. Copyright (c) 2006 S. Karger AG, Basel.