ADAM17
Encyclopedia
ADAM metallopeptidase domain 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa enzyme
that belongs to the ADAM protein
family of disintegrin
s and metalloproteases.
polypeptide.
Enzymes in this family are transmembrane
glycoproteins that are characterized by their conserved, multi-domain structure.
, and from within the intracellular membranes
of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase
' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors
, ligands, and enzymes.
revealed it to encode a 26 kDa type II transmembrane pro-polypeptide that becomes inserted into the cell membrane during its maturation. At the cell surface, pro-TNF-α is biologically active, and is able to induce immune responses via juxtacrine intercellular signaling. However, pro-TNF-α can undergo a proteolytic cleavage
at its Ala76-Val77 amide bond, which releases a soluble 17kDa extracellular domain (ectodomain
) from the pro-TNF-α molecule. This soluble ectodomain is the cytokine commonly known as TNF-α, which is of pivotal importance in paracrine signaling. This proteolytic liberation of soluble TNF-α is catalyzed by ADAM17.
, a cellular adhesion molecule
.
ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface, exists. The localization of mature ADAM17 to a perinulcear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.
, considerable investment has been made in the research into – and development of – anti-TNF-α agents, for the purpose of reducing the severity of inflammatory responses in disease states (e.g., the medicine etanercept
for treatment of rheumatoid arthritis
). The inhibition of ADAM17 by a pharmacological agent may represent another means by which the effects of TNF-α can be modulated, although this is yet to be demonstrated clinically in humans.
Functional ADAM17 has been documented to be ubiquitously expressed in the human colon
, with increased activity in the colonic mucosa of patients with ulcerative colitis
, a main form of inflammatory bowel disease
. These data will no doubt contribute to growing interest in the inhibition of ADAM17 as a potential therapeutic strategy.
experiments have provided evidence that suggests that ADAM17 may play a prominent role in the Notch signaling
pathway, during the proteolytic release of the Notch intracellular domain (from the Notch1 receptor) that occurs following ligand binding. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol
.
with MAPK1
, DLG1
and MAD2L1
.
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...
that belongs to the ADAM protein
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...
family of 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....
s and metalloproteases.
Chemical characteristics
ADAM17 is an 824-amino acidAmino 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...
polypeptide.
Enzymes in this family are transmembrane
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...
glycoproteins that are characterized by their conserved, multi-domain structure.
Functions
ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cellCell (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 from within the intracellular membranes
Intracellular membranes
Intracellular membranes are membranes inside the plasmalemma of the cell, comprising its endomembranous system. Typical examples include the nuclear envelope and the membrane of the endoplasmic reticulum....
of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase
Sheddase
Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface...
' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, ligands, and enzymes.
Interactions between ADAM17 and pro-TNF-α
Cloning of the TNF-α geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
revealed it to encode a 26 kDa type II transmembrane pro-polypeptide that becomes inserted into the cell membrane during its maturation. At the cell surface, pro-TNF-α is biologically active, and is able to induce immune responses via juxtacrine intercellular signaling. However, pro-TNF-α can undergo a proteolytic cleavage
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....
at its Ala76-Val77 amide bond, which releases a soluble 17kDa extracellular domain (ectodomain
Ectodomain
An ectodomain is the domain of a membrane protein that extends into the extracellular space . Ectodomains are usually the part of a protein that initiate contact with surface which leads to signal transduction. In SARS-CoV the ectodomain of the spike protein is responsible for attachment to and...
) from the pro-TNF-α molecule. This soluble ectodomain is the cytokine commonly known as TNF-α, which is of pivotal importance in paracrine signaling. This proteolytic liberation of soluble TNF-α is catalyzed by ADAM17.
Interactions between ADAM17 and L-selectin
ADAM17 has a role in the shedding of L-selectinL-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups...
, a cellular adhesion molecule
Cell adhesion molecule
Cell Adhesion Molecules are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix in the process called cell adhesion....
.
Cellular localization of ADAM17
The localization of ADAM17 is speculated to be an important determinant of shedding activity. TNF-α processing has classically been understood to occur in the trans-Golgi network, and be closely connected to transport of soluble TNF-α to the cell surface. However, research that suggests that the majority of mature, endogenousEndogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface, exists. The localization of mature ADAM17 to a perinulcear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.
ADAM17 as a target for future medicines?
Since TNF-α is a potent and pivotal mediator in the inflammatory processInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, considerable investment has been made in the research into – and development of – anti-TNF-α agents, for the purpose of reducing the severity of inflammatory responses in disease states (e.g., the medicine etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
for treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
). The inhibition of ADAM17 by a pharmacological agent may represent another means by which the effects of TNF-α can be modulated, although this is yet to be demonstrated clinically in humans.
Functional ADAM17 has been documented to be ubiquitously expressed in the human colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, with increased activity in the colonic mucosa of patients with ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
, a main form of inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
. These data will no doubt contribute to growing interest in the inhibition of ADAM17 as a potential therapeutic strategy.
Other points of interest
Recent in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
experiments have provided evidence that suggests that ADAM17 may play a prominent role in the Notch signaling
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...
pathway, during the proteolytic release of the Notch intracellular domain (from the Notch1 receptor) that occurs following ligand binding. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
Interactions
ADAM17 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with MAPK1
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...
, DLG1
DLG1
Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene....
and MAD2L1
MAD2L1
Mitotic spindle assembly checkpoint protein MAD2A is a protein that in humans is encoded by the MAD2L1 gene.-Interactions:MAD2L1 has been shown to interact with MAD2L2, CDC20, BUB1B, Estrogen receptor beta, ADAM17, UBD, CDC27 and Mad1....
.