|, AD10, AD18, CD156c, HsT18717, MADM, RAK, kuz, CDw156, ADAM metallopeptidase domain 10|
|RNA expression pattern|
|View/Edit Human||View/Edit Mouse|
|PDB structures||RCSB PDB PDBe PDBsum|
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 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.
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.
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 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.
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.
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.
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Entrez Gene: ADAM10 ADAM metallopeptidase domain 10".
- 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.
- 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.
- 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.
- "Entry of ADAM10 endopeptidase (EC-Number 22.214.171.124 )".
- 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.
- 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 . PMID 22553493.
- 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 . PMID 12460986.
- 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 . PMID 7593158.
- 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.
- "'Sheddase' helps the malaria parasite invade red blood cells".
- 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.
- "Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease". Journal of Clinical Investigation. 123: 2523–2538. doi:10.1172/JCI65401.
- Wolfsberg TG, Primakoff P, Myles DG, White JM (1995). "ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions.". J. Cell Biol. 131 (2): 275–8. doi:10.1083/jcb.131.2.275. PMC . PMID 7593158.
- O'Bryan JP, Fridell YW, Koski R, et al. (1995). "The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage.". J. Biol. Chem. 270 (2): 551–7. doi:10.1074/jbc.270.2.551. PMID 7822279.
- Howard L, Lu X, Mitchell S, et al. (1996). "Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types.". Biochem. J. 317 (1): 45–50. PMC . PMID 8694785.
- McKie N, Edwards T, Dallas DJ, et al. (1997). "Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes.". Biochem. Biophys. Res. Commun. 230 (2): 335–9. doi:10.1006/bbrc.1996.5957. PMID 9016778.
- Rosendahl MS, Ko SC, Long DL, et al. (1997). "Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases.". J. Biol. Chem. 272 (39): 24588–93. doi:10.1074/jbc.272.39.24588. PMID 9305925.
- Yamazaki K, Mizui Y, Tanaka I (1998). "Radiation hybrid mapping of human ADAM10 gene to chromosome 15.". Genomics. 45 (2): 457–9. doi:10.1006/geno.1997.4910. PMID 9344679.
- Yamazaki K, Mizui Y, Sagane K, Tanaka I (1998). "Assignment of a disintegrin and metalloproteinase domain 10 (Adam10) gene to mouse chromosome 9.". Genomics. 46 (3): 528–9. doi:10.1006/geno.1997.5043. PMID 9441766.
- Yavari R, Adida C, Bray-Ward P, et al. (1999). "Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia.". Hum. Mol. Genet. 7 (7): 1161–7. doi:10.1093/hmg/7.7.1161. PMID 9618175.
- Dallas DJ, Genever PG, Patton AJ, et al. (1999). "Localization of ADAM10 and Notch receptors in bone.". Bone. 25 (1): 9–15. doi:10.1016/S8756-3282(99)00099-X. PMID 10423016.
- Dias Neto E, Correa RG, Verjovski-Almeida S, et al. (2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC . PMID 10737800.
- Hattori M, Osterfield M, Flanagan JG (2000). "Regulated cleavage of a contact-mediated axon repellent.". Science. 289 (5483): 1360–5. doi:10.1126/science.289.5483.1360. PMID 10958785.
- Vincent B, Paitel E, Saftig P, et al. (2001). "The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein.". J. Biol. Chem. 276 (41): 37743–6. doi:10.1074/jbc.M105677200. PMID 11477090.
- Chubinskaya S, Mikhail R, Deutsch A, Tindal MH (2001). "ADAM-10 protein is present in human articular cartilage primarily in the membrane-bound form and is upregulated in osteoarthritis and in response to IL-1alpha in bovine nasal cartilage.". J. Histochem. Cytochem. 49 (9): 1165–76. doi:10.1177/002215540104900910. PMID 11511685.
- Lemjabbar H, Basbaum C (2002). "Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells.". Nature Medicine. 8 (1): 41–6. doi:10.1038/nm0102-41. PMID 11786905.
- Healy EF, Romano P, Mejia M, Lindfors G (September 2010). "Acetylenic inhibitors of ADAM10 and ADAM17: In silico analysis of potency and selectivity". J Mol Graph Model. 29 (3): 436–42. doi:10.1016/j.jmgm.2010.08.006. PMID 20863729.
- Arndt M, Lendeckel U, Röcken C, et al. (2002). "Altered expression of ADAMs (A Disintegrin And Metalloproteinase) in fibrillating human atria.". Circulation. 105 (6): 720–5. doi:10.1161/hc0602.103639. PMID 11839628.
- Colciaghi F, Borroni B, Pastorino L, et al. (2002). "[alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients.". Mol. Med. 8 (2): 67–74. PMC . PMID 12080182.
- Lim R, Winteringham LN, Williams JH, et al. (2002). "MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1.". J. Biol. Chem. 277 (43): 40997–1008. doi:10.1074/jbc.M206041200. PMID 12176995.
- Gatta LB, Albertini A, Ravid R, Finazzi D (2003). "Levels of beta-secretase BACE and alpha-secretase ADAM10 mRNAs in Alzheimer hippocampus.". NeuroReport. 13 (16): 2031–3. doi:10.1097/00001756-200211150-00008. PMID 12438920.
- Gutwein P, Mechtersheimer S, Riedle S, et al. (2003). "ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles.". FASEB J. 17 (2): 292–4. doi:10.1096/fj.02-0430fje. PMID 12475894.
- ADAM10 human gene location in the UCSC Genome Browser.
- ADAM10 human gene details in the UCSC Genome Browser.