Ectodomain Shedding & Sheddases & a whole bunch of Adams

December 31, 2023
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An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notable example of an ectodomain is the S protein, commonly known as the spike protein, of the viral particle responsible for the COVID-19 pandemic. The ectodomain region of the spike protein (S) is essential for attachment and eventual entry of the viral protein into the host cell.

Ectodomains play a crucial part in the signaling pathways of viruses. Recent findings have indicated that certain antibodies including the anti-receptor binding domain (anti-RBD) or anti-spike ectodomain (anti-ECD) IgG titers can act as virus neutralization titers (VN titers) which can be identified in individuals with diseases, dyspnea and hospitalizations. In perspective of severe acute respiratory syndrome corona virus 2 (SARS-Cov-2) these specific ectodomains may detect antibody efficacy against SARS-Cov-2, in which VN titers can classify eligible plasma donors. Protective measures against diseases and respiratory conditions can further be advanced through ongoing research on ectodomains. Ectodomain’s play a crucial part in the signaling pathways of viruses. In perspective of severe acute respiratory syndrome corona virus 2 (SARS-Cov-2) these specific ectodomains may detect antibody efficacy against SARS-Cov-2, in which VN titers can classify eligible plasma donors. Protective measures against diseases and respiratory conditions can further be advanced through ongoing research on ectodomains.

  • Salazar, Eric; Kuchipudi, Suresh V.; Christensen, Paul A.; Eagar, Todd; Yi, Xin; Zhao, Picheng; Jin, Zhicheng; Long, S. Wesley; Olsen, Randall J.; Chen, Jian; Castillo, Brian; Leveque, Christopher; Towers, Dalton; Lavinder, Jason; Gollihar, Jimmy; Cardona, Jose; Ippolito, Gregory; Nissly, Ruth; Bird, Ian; Greenawalt, Denver; Rossi, Randall M.; Gontu, Abhinay; Srinivasan, Sreenidhi; Poojary, Indira; Cattadori, Isabella M.; Hudson, Peter J.; Josleyn, Nicole M.; Prugar, Laura; Huie, Kathleen; Herbert, Andrew; Bernard, David W.; Dye, John M.; Kapur, Vivek; Musser, James M. (1 December 2020). “Convalescent plasma anti–SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization”. The Journal of Clinical Investigation. pp. 6728–6738. doi:10.1172/JCI141206. Retrieved 10 May 2022.

Ectodomains also interact with membrane systems inducing vesicle aggregation, lipid mixing and liposome leakage which provides information as to how certain viruses spread infection throughout the cellular domain. Specifically, the hepatitis C virus (HCV) utilize a fusion process in which the ectodomain of HCV E2 envelope protein confers fusogenic properties to membrane systems implying HCV infection proceeds throughout the cell through receptor mediated endocytosis. These findings in the role of the ectodomains interacting with target membranes give insight into virus destabilization and mechanism of the fusion of viral and cellular membrane which is yet to be further characterized.

Ectodomain shedding

It has become clear in the past years that ectodomain shedding is an initial step for the activation of specific receptors such as Notch, ErbB-4 and the angiopoietin receptor Tie-1. Notch-1 signaling is essential for endothelial differentiation, and tumor angiogenesis, while the angiopoietin receptor Tie-1 facilitates embryonic blood vessel formation. Upon binding of their ligands, Notch-1 and Tie-1 undergo proteolytic cleavage of the ectodomains by ADAM17 and ADAM10. This cleavage frees the cytoplasmic fragment for cellular signaling. In the case of Notch-1, it transfers to the nucleus.

ADAMs

ADAMs (short for a disintegrin and metalloproteinase) are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail. Nonetheless, not all human ADAMs have a functional protease domain, which indicates that their biological function mainly depends on protein–protein interactions. Those ADAMs which are active proteases 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, thereby activating it. ADAM genes are found in animals, choanoflagellates, fungi and some groups of green algae. Most green algae and all land plants likely lost ADAM proteins.

ADAMs are categorized under the EC 3.4.24.46 enzyme group, and in the MEROPS peptidase family M12B. The terms adamalysin and MDC family (metalloproteinase-like, disintegrin-like, cysteine rich) have been used to refer to this family historically. Therapeutic ADAM inhibitors might potentiate anti-cancer therapy. See also: ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family.

ADAMTS

ADAMTS (short for a disintegrin and metalloproteinase with thrombospondin motifs) is a family of multidomain extracellular protease enzymes. 19 members of this family have been identified in humans, the first of which, ADAMTS1, was described in 1997. Known functions of the ADAMTS proteases include processing of procollagens and von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan, making them key remodeling enzymes of the extracellular matrix. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. Homologous subfamily of ADAMTSL (ADAMTS-like) proteins, which lack enzymatic activity, has also been described. Most cases of thrombotic thrombocytopenic purpura arise from autoantibody-mediated inhibition of ADAMTS13. Like ADAMs, the name of the ADAMTS family refers to its disintegrin and metalloproteinase activity, and in the case of ADAMTS, the presence of a thrombospondin motif.

ADAMTS family members

Clinical findings and distribution of affected organs in individuals with Mendelian disorders caused by pathogenic mutations in different ADAMTS family genes. Predominant and recurrently reported clinical presentations of eight ADAMTS genes with a strong causal relationship to Mendelian disorders are marked according to organ. Heterogeneous distribution of affected organ types indicates the phenotypic heterogeneity among hereditary disorders caused by pathogenic germline mutations in ADAMTS genes. From Rim JH, Choi YJ, Gee HY (March 2020). “Genomic Landscape and Mutational Spectrum of ADAMTS Family Genes in Mendelian Disorders Based on Gene Evidence Review for Variant Interpretation”. Biomolecules. 10 (3): 449. doi:10.3390/biom10030449. PMC 7175297. PMID 32183147.

See also: A disintegrin and metalloproteinase (ADAM) family and ADAMTSL family (ADAMTS-like proteins)

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.

ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell, 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.

Cloning of the TNF-α gene 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.

Recently, ADAM17 was discovered as a crucial mediator of resistance to radiotherapy. Radiotherapy can induce a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which results in enhanced ADAM17 activity in vitro and in vivo. It was also shown that radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and radiotherapy-induced treatment resistance.

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. ADAM17 also regulates the MAP kinase signaling pathway by regulating shedding of the EGFR ligand amphiregulin in the mammary gland. ADAM17 also has a role in the shedding of L-selectin, a cellular adhesion molecule.

ADAM17 has been shown to interact with:

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. Shedding is also associated with clustering of ADAM17 with its substrate, membrane bound TNF, in lipid rafts.  The overall process is called substrate presentation and regulated by cholesterol. Research also suggests that the majority of mature, endogenous ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface. The localization of mature ADAM17 to a perinuclear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.

  • Tellier, Edwige; Canault, Matthias; Rebsomen, Laure; Bonardo, Bernadette; Juhan-Vague, Irène; Nalbone, Gilles; Peiretti, Franck (10 December 2006). “The shedding activity of ADAM17 is sequestered in lipid rafts”. Experimental Cell Research. 312 (20): 3969–3980. doi:10.1016/j.yexcr.2006.08.027. PMID 17010968.

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. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol.

  • Taïeb J, Delarche C, Ethuin F, Selloum S, Poynard T, Gougerot-Pocidalo MA, Chollet-Martin S (December 2002). “Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils”. Journal of Leukocyte Biology. 72 (6): 1142–7. doi:10.1189/jlb.72.6.1142. PMID 12488495. S2CID 9712196.

Adam17 may facilitate entry of the SARS‑CoV‑2 virus, possibly by enabling fusion of virus particles with the cytoplasmic membrane. Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles. Adam17 sheddase activity may contribute to COVID-19 inflammation by cleavage of TNF-α and Interleukin-6 receptor.

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.

Members of the ADAM family are cell surface proteins with a unique structure, possessing both potential adhesion and protease domains. Sheddase, a generic name for the ADAM metallopeptidase, functions primarily to cleave membrane proteins at the cellular surface. Once cleaved, the sheddases release soluble ectodomains with an altered location and function.

Although a single sheddase may “shed” a variety of substances, multiple sheddases can cleave the same substrate resulting in different consequences. This gene encodes an ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin. ADAM10 (EC#: 3.4.24.81) is a sheddase, and has a broad specificity for peptide hydrolysis reactions. ADAM10 cleaves ephrin, within the ephrin/eph complex, formed between two cell surfaces. When ephrin is freed from the opposing cell, the entire ephrin/eph complex is endocytosed. This shedding in trans had not been previously shown, but may well be involved in other shedding events. In neurons, ADAM10 is the most important enzyme, with α-secretase activity for proteolytic processing of the amyloid precursor protein. ADAM10, along with ADAM17, cleaves the ectodomain of the triggering receptor expressed on myeloid cells 2 (TREM2), to produce soluble TREM2 (sTREM2), which has been proposed as a CSF and sera biomarker of neurodegeneration. ADAM10 belongs to subfamily A, the most ancestral subfamily of ADAM proteins, which is shared by all major groups of animals, choanoflagellates, fungi, and green algae from the class Mamiellophyceae.

Although no crystallographic x-ray diffraction analyses have been published that depict the entire structure of ADAM10, one domain has been studied using this technique. The disintegrin and cysteine-rich domain (shown to the right) plays an essential role in regulation of protease activity in vivo. Recent experimental evidence suggests that this region, which is distinct from the active site, may be responsible for substrate specificity of the enzyme. It is proposed that this domain binds to particular regions of the enzyme’s substrate, allowing peptide bond hydrolysis to occur in well defined locations on certain substrate proteins.

The proposed active site of ADAM10 has been identified by sequence analysis, and is identical to enzymes in the Snake Venom metalloprotein domain family. The consensus sequence for catalytically active ADAM proteins is HEXGHNLGXXHD. Structural analysis of ADAM17, which has the same active site sequence as ADAM10, suggests that the three histidines in this sequence bind a Zn2+ atom, and that the glutamate is the catalytic residue.

Although the exact mechanism of ADAM10 has not been thoroughly investigated, its active site is homologous to those of well studied zinc-proteases such as carboxypeptidase A and thermolysin. Therefore, it is proposed that ADAM10 utilizes a similar mechanism as these enzymes. In zinc proteases, the key catalytic elements have been identified as a glutamate residue and a Zn2+ ion coordinated to histidine residues. The proposed mechanism begins with deprotonation of a water molecule by glutamate. The resultant hydroxide initiates a nucleophilic attack on a carbonyl carbon on the peptide backbone, producing a tetrahedral intermediate. This step is facilitated by electron withdrawal from oxygen by Zn2+ and by zinc’s subsequent stabilization of the negative charge on the oxygen atom in the intermediate state. As electrons move down from the oxygen atom to re-form the double bond, the tetrahedral intermediate collapses to products with protonation of -NH by the glutamate residue.

  • Lolis E, Petsko GA (1990). “Transition-state analogues in protein crystallography: probes of the structural source of enzyme catalysis”. Annual Review of Biochemistry. 59: 597–630. doi:10.1146/annurev.bi.59.070190.003121. PMID 2197984.

ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer’s Disease.

  • Marcello E, Borroni B, Pelucchi S, Gardoni F, Di Luca M (November 2017). “ADAM10 as a therapeutic target for brain diseases: from developmental disorders to Alzheimer’s disease”. Expert Opinion on Therapeutic Targets. 21 (11): 1017–1026. doi:10.1080/14728222.2017.1386176. PMID 28960088. S2CID 46800368.

A number of different proteins on the surface of Plasmodium falciparum malaria parasites help the invaders bind to red blood cells. But once attached to host blood cells, the parasites need to shed the ‘sticky’ surface proteins that would otherwise interfere with entrance into the cell. The Sheddase enzyme, specifically called PfSUB2 in this example, is required for the parasites to invade cells; without it, the parasites die. The sheddase is stored in and released from cellular compartments near the tip of the parasite, according to the study. Once on the surface, the enzyme attaches to a motor that shuttles it from front to back, liberating the sticky surface proteins. With these proteins removed, the parasite gains entrance into a red blood cell. The entire invasion lasts about 30 seconds and without this ADAM metallopeptidase, malaria would be ineffective at invading the red blood cells.

In combination with low doses of herceptin, selective ADAM10 inhibitors decrease proliferation in HER2 over-expressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating breast cancer and a variety of other cancers with active HER2 signaling.

The presence of the product of this gene in neuronal synapses in conjunction with protein AP2 has been seen in increased amounts in the hippocampal neurons of Alzheimer’s disease patients.

ProteinDescription
ADAM1ADAM1 (fertilin α) is a subunit of an integral sperm membrane heterodimeric glycoprotein called fertilin,
which plays an important role in sperm-egg interactions.
ADAM2ADAM2 (fertilin β) is a subunit of an integral sperm
membrane heterodimeric glycoprotein called fertilin,
which plays an important role in sperm-egg interactions.
 “Entrez Gene: ADAM2 ADAM metallopeptidase domain 2 (fertilin beta)”
ADAM7ADAM7 is a transmembrane protein important for the
maturation of sperm cells in mammals. ADAM7 is also
denoted as: ADAM_7, ADAM-7, EAPI, GP-83, and GP83.
“Entrez Gene: ADAM metallopeptidase domain 7”.
ADAM8The ADAM8 protein encoded by this gene may be
involved in cell adhesion during neurodegeneration.
“Entrez Gene: ADAM8 ADAM metallopeptidase domain 8”.
ADAM9The ADAM9 protein encoded by this gene interacts
with SH3 domain-containing proteins, binds mitotic
arrest deficient 2 beta protein, and is also involved in TPA-induced ectodomain shedding of membrane-anchored
heparin-binding EGF-like growth factor. “Entrez Gene: ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma)”.
ADAM10ADAM10 (EC#: 3.4.24.81) is a sheddase, and has a broad
specificity for peptide hydrolysis reactions. “Entry of ADAM10 endopeptidase (EC-Number 3.4.24.81 )”.
ADAM11The ADAM11 gene represents a candidate tumor suppressor
gene for human breast cancer based on its location within
a minimal region of chromosome 17q21 previously defined by tumor deletion mapping.
“Entrez Gene: ADAM11 ADAM metallopeptidase domain 11”.
ADAM12ADAM12, a metalloprotease that binds insulin growth factor
binding protein-3 (IGFBP-3), appears to be an effective
early Down syndrome marker.
Danforth’s Obstetrics and Gynecology, 10th Edition;
Copyright 2008 Lippincott Williams & Wilkins; Chapter 7:
Prenatal Diagnosis, Page 113
ADAM15Through its disintegrin-like domain, this protein specifically
interacts with the integrin beta chain, beta 3. It also interacts
with Src family protein–tyrosine kinases in a 
phosphorylation-dependent manner, suggesting that
this protein may function in cell-cell adhesion as well as
in cellular signaling.
“Entrez Gene: ADAM15 ADAM metallopeptidase domain 15 (metargidin)”.
ADAM17ADAM17 is understood to be involved in the processing
of tumor necrosis factor alpha (TNF-α) at the surface of the cell,
and from within the intracellular membranes of the 
trans-Golgi network. ADAM17 also has a role in the
shedding of L-selectin, a cellular adhesion molecule.
Li Y, Brazzell J, Herrera A, Walcheck B (October 2006). 
“ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding”. Blood. 108 (7): 2275–9. doi:10.1182/blood-2006-02-005827. PMC 1895557. PMID 16735599.
ADAM18The protein encoded by this gene is a sperm surface protein. 
Synonymous with ADAM27.  
“Entrez Gene: ADAM18 ADAM metallopeptidase domain 18”.
ADAM19This member is a type I transmembrane protein and serves
as a marker for dendritic cell differentiation. It has also been
demonstrated to be an active metalloproteinase, which may
be involved in normal physiological and pathological processes
such as cells migration, cell adhesion, cell-cell and
cell-matrix interactions, and signal transduction.
“Entrez Gene: ADAM19 ADAM metallopeptidase domain 19 (meltrin beta)”.
ADAM20Exclusively expressed in the testes.
ADAM21Note: Synonymous with ADAM31.
ADAM22This gene is highly expressed in the brain and may function
as an integrin ligand in the brain.
“Entrez Gene: ADAM22 ADAM metallopeptidase domain 22”.
ADAM23This gene is highly expressed in the brain and may function
as an integrin ligand in the brain.
“Entrez Gene: ADAM23 ADAM metallopeptidase domain 23”.
ADAM28The protein encoded by this gene is a lymphocyte-expressed
ADAM protein.
“Entrez Gene: ADAM28 ADAM metallopeptidase domain 28”.
ADAM29
ADAM30
ADAM33This protein is a type I transmembrane protein implicated
in asthma and bronchial hyperresponsiveness.
“Entrez Gene: ADAM33 ADAM metallopeptidase domain 33”.

Many cytokines and growth factors are synthesized as membrane-bound proforms which undergo proteolytic shedding for activation. The ephrins EPH receptor A2 and A3 are shed by ADAM10, creating cleaved soluble Eph receptors, which inhibit tumor angiogenesis in mice. Additional examples are the proteolytic shedding of soluble E-selectin, shedding of urokinase receptor (uPAR) by MMP-12 creating soluble uPAR which has chemotactic properties for leukocytes and progenitor cells, and the shedding of interleukin-6 receptors by ADAM10 and ADAM17 which facilitates interleukin-6 signaling in endothelial cells. Semaphorin 4D is cleaved from its membrane-bound form by MT1-MMP (MMP-14) in tumor cells; it then interacts with plexin B1 on endothelial cells, promoting pro-angiogenic chemotaxis.

Shedding of a membrane-anchored cytokine or growth factor by ADAM proteinases may be relevant for various signal transduction events. Alternatively, shedding may be required for the ligand to diffuse to distant receptors. Shedding may be required for the down regulation of signals by removing signaling ligands, or cleavage and release of receptors. Release of the receptor may also generate soluble receptors which act as decoys by sequestering ligands. These findings indicate that ectodomain shedding is a ubiquitous process facilitating a wide variety of cellular events involved in angiogenesis. Because potent biological modifiers are generated, it is likely controlled by highly regulated mechanism. Along with ADAMs and MT-MMPs, membrane-bound serine proteases also may play a role in ectodomain shedding.

Sheddases

Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface. Many sheddases are members of the ADAM 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[clarification needed] the yield of agonists. Sheddase inhibitors active on ADAM10 and ADAM17 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 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 Immunoglobulin 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) 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.

See also

References

  1. R&D Systems (Winter 2006). “Need help at the cell surface? Ask your local sheddase”. Cytokine Bulletin.
  2. Healthvalue: Sheddases and ADAMs
  3. Sommer, Anselm; Kordowski, Felix; Büch, Joscha; Maretzky, Thorsten; Evers, Astrid; Andrä, Jörg; Düsterhöft, Stefan; Michalek, Matthias; Lorenzen, Inken (2016-05-10). “Phosphatidylserine exposure is required for ADAM17 sheddase function”. Nature Communications. 7. doi:10.1038/ncomms11523. ISSN 2041-1723. PMC 4866515. PMID 27161080.
  4. “ADAM10 is a principal ‘sheddase’ of the low-affinity immunoglobulin E receptor CD23” (PDF). Retrieved November 5, 2016.
  5. “Sheddase Activity of Tumor Necrosis Factor- Converting Enzyme Is Increased and Prognostically Valuable in Head and Neck Cancer”. Retrieved 2016-11-05.

Further reading

Hydrolase: proteases (EC 3.4)
Enzymes

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