Assembly, trafficking and function of gamma-secretase

gamma-Secretase catalyzes the final cleavage of the beta-amyloid
precursor protein to generate amyloid-beta peptide, the principal
component of amyloid plaques in the brains of patients suffering
from Alzheimer's disease. Here, we review the identification of
gamma-secretase as a protease complex and its assembly and
trafficking to its site(s) of cellular function. In reconstitution
experiments, gamma-secretase was found to be composed of four
integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2
and APH-1 that are essential and sufficient for gamma-secretase
activity. PS, which serves as a catalytic subunit of
gamma-secretase, was identified as a prototypic member of novel
aspartyl proteases of the GxGD type. In human cells,
gamma-secretase could be further defined as a heterogeneous
activity consisting of distinct complexes that are composed of PS1
or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2.
Using green fluorescent protein as a reporter we localized PS and
gamma-secretase activity at the plasma membrane and endosomes.
Investigation of gamma-secretase complex assembly in knockdown and
knockout cells of the individual subunits allowed us to develop a
model of complex assembly in which NCT and APH-1 first stabilize PS
before PEN-2 assembles as the last component. Furthermore, we could
map domains in PS and PEN-2 that govern assembly and trafficking of
the complex. Finally, Rer1 was identified as a PEN-2-binding
protein that serves a role as an auxiliary factor for
gamma-secretase complex assembly. Copyright (c) 2006 S. Karger AG,
Basel.