The gamma secretase complex, with
nicastrin (red),
presenilin-1 (orange),
PEN-2 (blue), and
APH-1 (green); lumenal membrane shown in red and cytoplasmic membrane shown in blue. The structure was solved by
cryo-electron microscopy.[1]
The gamma secretase complex consists of four individual proteins:
PSEN1 (presenilin-1),[8]nicastrin,
APH-1 (anterior pharynx-defective 1), and
PEN-2 (presenilin enhancer 2).[9] Recent evidence suggests that a fifth protein, known as
CD147, is a non-essential regulator of the complex whose absence increases activity.[10][11]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 [12] and modulates immune cell activity.[13] 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.[14]
The proteins 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.[15] PEN-2 associates with the complex via binding of a transmembrane domain of presenilin[16] and, among other possible roles, helps to stabilize the complex after presenilin proteolysis has generated the activated
N-terminal and
C-terminal fragments.[17] APH-1, which is required for proteolytic activity, binds to the complex via a
conservedalpha helix interaction
motif and aids in initiating assembly of premature components.[18]
The gamma secretase complex is thought to assemble and mature via proteolysis in the early
endoplasmic reticulum.[20] The complexes are then transported to the late ER where they interact with and cleave their substrate proteins.[21] Gamma secretase complexes have also been observed localized to the
mitochondria, where they may play a role in promoting
apoptosis.[22]
Function
Gamma secretase 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 where the catalytic
aspartate residue is located. 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.[23] Low-resolution
electron microscopy reconstructions have allowed the visualization of the hypothesized internal pores of about 2 nanometres.[24] In 2014, a three-dimensional structure of an intact human gamma-secretase complex was determined by
cryo-electron microscopy single-particle analysis at 4.5 angstrom resolution[25] and in 2015 an atomic-resolution (3.4 angstrom) cryo-EM structure was reported.[1]
The gamma 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 of variable length, most typically 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.[26] Although older data suggested that different forms of the gamma secretase complex could be differentially responsible for generating different amyloid beta isoforms,[27] current evidence indicates that the C-terminus of amyloid beta is produced by a series of single-residue cleavages by the same gamma secretase complex.[28][29][30] Earlier cleavage sites produce peptides of length 46 (zeta-cleavage) and 49 (epsilon-cleavage).[29]
^Zhou S, Zhou H, Walian PJ, Jap BK (April 2006). "The discovery and role of CD147 as a subunit of gamma-secretase complex". Drug News Perspect. 19 (3): 133–8.
doi:
10.1358/dnp.2006.19.3.985932.
PMID16804564.
^Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P (April 2006). "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 (7088): 1208–12.
doi:
10.1038/nature04667.
PMID16641999.
S2CID4349251.
^Farfara D, Trudler D, Segev-Amzaled N, Galron R, Stein R, Frenkel D (November 2010). "g secretase component presenilin is important for microglia b-Amyloid clearance". Annals of Neurology. 69 (1): 170–80.
doi:
10.1002/ana.22191.
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