Alpha secretase
Encyclopedia
Alpha secretases are a family of proteolytic
enzyme
s that cleave amyloid precursor protein
(APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease
-associated peptide
amyloid beta
when APP is instead processed by beta secretase and gamma secretase
. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM
('a disintegrin
and metalloprotease domain') family, which are expressed on the surfaces of cells
and anchored in the cell membrane
. Several such proteins, notably ADAM10
, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.
ADAM10 consists of two protein domain
s, a disintegrin domain and a prodomain; however, only the prodomain is required for APP processing. Other ADAM proteins, ADAM17
(also called TACE, tumor necrosis factor-α converting enzyme), ADAM9
, and ADAM19
have also been identified as alpha secretases; extracellular expression of mutant ADAM9 (also known as MDC9 or meltrin gamma) lacking the membrane anchor domain has been suggested as one of many possible means of Alzheimer's prevention and treatment exploiting the alpha secretase pathway. Two distinct modalities of alpha-secretase activity have been observed in cells; constitutive activity occurs mainly at the cell surface and is independent of regulatory mechanisms inside the cell, while regulated activity occurs mainly in the golgi
and is dependent on the activity of protein kinase C
. Alpha-secretase activity in the golgi is thought to compete directly with the beta-secretase pathway for APP substrate
s during membrane protein maturation. Cell-surface cleavage by alpha secretase is very rapid after APP reaches the cell surface.
The activity of alpha secretases has been implicated in the regulation of learning and memory
formation. Release of the APPsα ectodomain has neurotrophic effects that counteract apoptotic
signaling and promote synapse
formation, processes that are upregulated when ADAM10 is overexpressed. Alpha secretase activity has also been observed to be upregulated in response to the signaling peptide
PACAP.
Related alpha-secretases, including ADAM10, have also been implicated in similar maturation events for other transmembrane protein
s such as MHC class I
proteins. Recent evidence suggests that some such proteins are first processed to ectodomains by alpha secretases and subsequently cleaved by another Alzheimer's-associated protease complex
, gamma secretase
in its presenilin
-complexed form. The Notch pathway
bears many similarities to APP processing and is also regulated in part by ADAM10.
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...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that cleave 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) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the 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...
-associated 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...
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...
when APP is instead processed by beta secretase and gamma secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM
ADAM Protein
ADAM is a family of peptidase proteins. It is also known as the adamalysin family or MDC family. ADAMs are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, activating it...
('a disintegrin
Disintegrin
Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion....
and metalloprotease domain') family, which are expressed on the surfaces of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
and anchored in 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...
. Several such proteins, notably ADAM10
ADAM10
Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.- Function :...
, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
s, a disintegrin domain and a prodomain; however, only the prodomain is required for APP processing. Other ADAM proteins, ADAM17
ADAM17
ADAM metallopeptidase domain 17 , also called TACE , is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.- Chemical characteristics :...
(also called TACE, tumor necrosis factor-α converting enzyme), ADAM9
ADAM9
Disintegrin and metalloproteinase domain-containing protein 9 is an enzyme that in humans is encoded by the ADAM9 gene.-Interactions:ADAM9 has been shown to interact with MAD2L2, SNX9 and SH3GL2.-External links:...
, and ADAM19
ADAM19
ADAM19 , is a human gene.-Further reading:...
have also been identified as alpha secretases; extracellular expression of mutant ADAM9 (also known as MDC9 or meltrin gamma) lacking the membrane anchor domain has been suggested as one of many possible means of Alzheimer's prevention and treatment exploiting the alpha secretase pathway. Two distinct modalities of alpha-secretase activity have been observed in cells; constitutive activity occurs mainly at the cell surface and is independent of regulatory mechanisms inside the cell, while regulated activity occurs mainly in the golgi
Golgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
and is dependent on the activity of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
. Alpha-secretase activity in the golgi is thought to compete directly with the beta-secretase pathway for APP substrate
Substrate (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...
s during membrane protein maturation. Cell-surface cleavage by alpha secretase is very rapid after APP reaches the cell surface.
The activity of alpha secretases has been implicated in the regulation of learning and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
formation. Release of the APPsα ectodomain has neurotrophic effects that counteract apoptotic
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...
signaling and promote synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
formation, processes that are upregulated when ADAM10 is overexpressed. Alpha secretase activity has also been observed to be upregulated in response to the signaling 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...
PACAP.
Related alpha-secretases, including ADAM10, have also been implicated in similar maturation events for other 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 such as MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
proteins. Recent evidence suggests that some such proteins are first processed to ectodomains by alpha secretases and subsequently cleaved by another Alzheimer's-associated protease complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
, gamma secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
in its presenilin
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...
-complexed form. The Notch pathway
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...
bears many similarities to APP processing and is also regulated in part by ADAM10.