is a multi-subunit protease complex, itself an integral membrane
protein, that cleaves single-pass transmembrane proteins at residues
within the transmembrane domain. The most well-known substrate
of gamma secretase is amyloid precursor protein, a large integral
membrane protein that, when cleaved by both gamma and beta secretase,
produces a short 39-42 amino acid peptide called amyloid beta
whose abnormally folded fibrillar form is the primary component
of amyloid plaques found in the brains of Alzheimer's disease
patients. Gamma secretase is also critical in the related processing
of the Notch protein.
secretase complex has not yet been fully characterized but minimally
consists of four individual proteins: presenilin, nicastrin, APH-1
(anterior pharynx-defective 1), and PEN-2 (presenilin enhancer
evidence suggests that a fifth protein, known as CD147, is a non-essential
regulator of the complex whose absence increases activity. Presenilin,
an aspartyl protease, is the catalytic subunit; mutations in the
presenilin gene have been shown to be a major genetic risk factor
for Alzheimer's disease.
In humans, two forms of presenilin and two forms of APH-1 have
been identified in the genome; one of the APH homologs can also
be expressed in two isoforms via alternative splicing, leading
to at least six different possible gamma secretase complexes that
may have tissue- or cell type specificity.
in the gamma secretase complex are heavily modified by proteolysis
during assembly and maturation of the complex; a required activation
step is in the autocatalytic cleavage of presenilin to N- and
C-terminal fragments. Nicastrin's primary role is in maintaining
the stability of the assembled complex and regulating intracellular
protein trafficking. PEN-2 associates with
the complex via binding of a transmembrane domain of presenilin
and, among other possible roles, helps to stabilize the complex
after presenilin proteolysis has generated the activated N-terminal
and C-terminal fragments.
APH-1, which is required for proteolytic activity, binds to the
complex via a conserved alpha helix interaction motif and aids
in initiating assembly of premature components.
secretase complex is thought to assemble and mature via proteolysis
in the early endoplasmic reticulum.
The complexes are then transported to the late ER where they interact
with and cleave their substrate proteins.
Gamma secretase complexes have also been observed localized to
the mitochondria, where they may play a role in promoting apoptosis.
is an internal protease that cleaves within the membrane-spanning
domain of its substrate proteins, including amyloid precursor protein (APP) and Notch.
Substrate recognition occurs via nicastrin ectodomain binding
to the N-terminus of the target, which is then passed via a poorly
understood process between the two presenilin fragments to a water-containing
active site at which the catalytic aspartate residue resides.
The active site must contain water to carry out hydrolysis within
a hydrophobic environment in the interior of the cell membrane,
although it is not well understood how water and proton exchange
is effected, and as yet no X-ray crystallography structure of
gamma secretase is available. Low-resolution
electron microscopy reconstructions have allowed the visualization
of the hypothesized internal pores of about 2 nanometres.
secretase complex is unusual among proteases in having a "sloppy"
cleavage site at the C-terminal site in amyloid beta generation; gamma
secretase can cleave APP in any of multiple sites to generate
a peptide from 39 to 42 amino acids long, with Aβ40 the most
common isoform and Aβ42 the most susceptible to conformational
changes leading to amyloid fibrillogenesis. Certain mutations
in both APP and in both types of human presenilin are associated
with increased Aβ42 production and the early-onset genetic form
of familial Alzheimer's disease.
Some evidence has suggested that different forms of the gamma
secretase complex are differentially responsible for generating
different amyloid beta isoforms;
however, very recent research indicates that the C-terminus of
amyloid beta is produced by a series of single-residue cleavages
by the same isoform, beginning with the generation of Aβ46.
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