Gamma secretase
Encyclopedia
Gamma secretase is a multi-subunit protease
complex, itself an integral membrane protein
, that cleaves single-pass transmembrane protein
s at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases
. 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 17-42 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.
, nicastrin
, APH-1
(anterior pharynx-defective 1), and PEN-2
(presenilin enhancer 2). Recent 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.
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. 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.
Recent research has shown that interaction of the gamma secretase complex with the γ-secretase activating protein
facilitates the gamma cleavage of amyloid precursor protein
into β-amyloid.
. 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
.
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.
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 from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to conformational change
s 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.
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
complex, itself an integral membrane protein
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...
, that cleaves single-pass transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
s at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases
Intramembrane protease
Intramembrane proteases are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid...
. The most well-known substrate of gamma secretase is amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 17-42 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
called amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
whose abnormally folded
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
patients. Gamma secretase is also critical in the related processing of the Notch
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
protein.
Subunits and assembly
The gamma secretase complex has not yet been fully characterized but minimally consists of four individual proteins: presenilinPresenilin
Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...
, nicastrin
Nicastrin
Nicastrin, also known as NCSTN, is a protein which in humans is encoded by the NCSTN gene.Nicastrin is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein to the short Alzheimer's disease-associated peptide...
, APH-1
APH-1
APH-1 is a protein gene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin...
(anterior pharynx-defective 1), and PEN-2
PEN-2
PEN-2 is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein . The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic...
(presenilin enhancer 2). Recent 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
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
subunit; mutations in the presenilin gene have been shown to be a major genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
risk factor for Alzheimer's disease. In humans, two forms of presenilin and two forms of APH-1 have been identified in the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
; one of the APH homologs
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
can also be expressed in two isoforms via alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity.
The proteins in the gamma secretase complex are heavily modified by proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
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
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
interaction motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
and aids in initiating assembly of premature components.
Recent research has shown that interaction of the gamma secretase complex with the γ-secretase activating protein
Protein pigeon homolog
Protein pigeon homolog also known as gamma-secretase activating protein is a protein that in humans is encoded by the PION gene.- Gene :...
facilitates the gamma cleavage of amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
into β-amyloid.
Cellular trafficking
The gamma secretase complex is thought to assemble and mature via proteolysis in the early endoplasmic reticulumEndoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Function
Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its substrateSubstrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
proteins, including amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(APP) and Notch
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
. 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
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
-containing active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
at which the catalytic aspartate residue resides. The active site must contain water to carry out hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
within a hydrophobic environment in the interior of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, although it is not well understood how water and proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
exchange is effected, and as yet no X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
structure of gamma secretase is available. Low-resolution electron microscopy reconstructions have allowed the visualization of the hypothesized internal pores of about 2 nanometres.
The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
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 change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
s leading to amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
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.