Sheddases are membrane-bound

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

s that cleave extracellular portions of

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

s, releasing the soluble ectodomains from the cell surface. Many sheddases are members of the

ADAM Adam; el, Ἀδάμ, Adám; la, Adam is the name given in Genesis 1-5 to the first human. Beyond its use as the name of the first man, ''adam'' is also used in the Bible as a pronoun, individually as "a human" and in a collective sense as " ...

or aspartic protease ( BACE) protein families. These enzymes can activate a transmembrane protein if it is a receptor (e.g., HER2), or cut off the part of the transmembrane protein which has already bound an agonist (e.g., in the case of EGFR), allowing this agonist to go and stimulate a receptor on another cell. Hence, sheddases demultiply the yield of agonists. Sheddase inhibitors active on

ADAM10 A 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 Members of the ADAM family are cell surface proteins with a uniq ...

and

ADAM17 A disintegrin and metalloprotease 17 (ADAM17), also called TACE (''tumor necrosis factor-α-converting enzyme''), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases. Chemical characteristics ADAM1 ...

can potentiate anti-cancer therapy.

Functions

It has been postulated that the activity of sheddases occurs in relation to the amount of general enzymatic activity. Research indicates that sheddases are instead related to

phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via a ...

exposure. When PSA-3 cells' ability to synthesize phosphatidylserine was repressed, sheddase activity decreased, and the sheddase activity returned to normal levels when the cells were again able to synthesize phosphatidylserine. This led researchers to conclude that phosphatidyserine exposure is necessary for cells to exhibit sheddase activity.

Uses

Due to the nature of the mechanisms and functions of sheddase enzymes, they have been studied on the basis of discovering possible uses in medicine. One such use is in the treatment of allergic responses and other processes of the immune system. ADAM10 is responsible for the shedding of the

CD23 CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD ...

Immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

receptor, which releases soluble sCD23. sCD23 present in the blood serum contributes to immune response and, to some, the onset of inflammatory disease such as asthma. Given that ADAM10 sheddase cleaves CD23 and increases the levels of sCD23, possible treatments for these diseases may center around the inhibition of sheddase function. Tumor necrosis factor alpha converting enzyme (TACE) is a sheddase protein that has been observed in many types of cancer and could serve as an important

Biomarker (medicine) In medicine, a biomarker is a measurable indicator of the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an or ...

used in the detection of cancer. While the expression of TACE does not directly correlate with particular stages of cancer, the shedding activity of the enzyme is significantly more prominent in head and neck cancer cells compared to normal cultured cells.

References

EC 3.4 Membrane proteins {{membrane-protein-stub

Functions

Uses

See also

References