Available structures
PDBOrtholog search: PDBe RCSB
Aliases ADAM10, AD10, AD18, CD156c, HsT18717, MADM, RAK, kuz, CDw156, ADAM metallopeptidase domain 10
External IDs MGI: 109548 HomoloGene: 865 GeneCards: ADAM10
RNA expression pattern

More reference expression data
Species Human Mouse









RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 15: 58.59 – 58.75 Mb Chr 9: 70.68 – 70.78 Mb
PubMed search [1] [2]
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ADAM10 endopeptidase
EC number
CAS number 193099-09-1
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

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.[3]


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.[4][5][6]

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.[3]

ADAM10 (EC#: is a sheddase, and has a broad specificity for peptide hydrolysis reactions.[7]

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.[8]

In neurons, ADAM10 is the most important enzyme with α-secretase activity for proteolytic processing of the amyloid precursor protein.[9]


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 disintigrin 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.[10]

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.[11]

Catalytic Mechanism

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.[12]

The proposed mechanism begins with deprotonation of a water molecule by glutamate. The resultant hydroxide initiates a nucleophillic 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.[12]

Clinical significance

Interaction with the malaria parasite

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.[13]

Breast cancer

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.[14]

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.[15]

See also


  1. "Human PubMed Reference:".
  2. "Mouse PubMed Reference:".
  3. 1 2 "Entrez Gene: ADAM10 ADAM metallopeptidase domain 10".
  4. Moss ML, Bartsch JW (June 2004). "Therapeutic benefits from targeting of ADAM family members". Biochemistry. 43 (23): 7227–35. doi:10.1021/bi049677f. PMID 15182168.
  5. Nagano O, Saya H (December 2004). "Mechanism and biological significance of CD44 cleavage". Cancer Sci. 95 (12): 930–5. doi:10.1111/j.1349-7006.2004.tb03179.x. PMID 15596040.
  6. Blobel CP (January 2005). "ADAMs: key components in EGFR signalling and development". Nature Reviews Molecular Cell Biology. 6 (1): 32–43. doi:10.1038/nrm1548. PMID 15688065.
  7. "Entry of ADAM10 endopeptidase (EC-Number )".
  8. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB (October 2005). "Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans". Cell. 123 (2): 291–304. doi:10.1016/j.cell.2005.08.014. PMID 16239146.
  9. Haass, C.; Kaether, C.; Thinakaran, G.; Sisodia, S. (2012). "Trafficking and Proteolytic Processing of APP". Cold Spring Harbor perspectives in medicine. 2 (5): a006270. doi:10.1101/cshperspect.a006270. PMC 3331683Freely accessible. PMID 22553493.
  10. Smith KM, Gaultier A, Cousin H, Alfandari D, White JM, DeSimone DW (December 2002). "The cysteine-rich domain regulates ADAM protease function in vivo". The Journal of Cell Biology. 159 (5): 893–902. doi:10.1083/jcb.200206023. PMC 2173380Freely accessible. PMID 12460986.
  11. Wolfsberg TG, Primakoff P, Myles DG, White JM (October 1995). "ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions". The Journal of Cell Biology. 131 (2): 275–8. doi:10.1083/jcb.131.2.275. PMC 2199973Freely accessible. PMID 7593158.
  12. 1 2 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/ PMID 2197984.
  13. "'Sheddase' helps the malaria parasite invade red blood cells".
  14. Liu PC, Liu X, Li Y, et al. (June 2006). "Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells". Cancer Biology & Therapy. 5 (6): 657–64. doi:10.4161/cbt.5.6.2708. PMID 16627989.
  15. "Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease". Journal of Clinical Investigation. 123: 2523–2538. doi:10.1172/JCI65401.

Further reading

External links

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