ADAM10

ADAM metallopeptidase domain 10, also known as ADAM10, is a human gene.cite web | title = Entrez Gene: ADAM10 ADAM metallopeptidase domain 10| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=102| accessdate = ]

PBB_Summary
section_title =
summary_text = 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.cite web | title = R&D Systems: NEED HELP AT THE CELL SURFACE? ASK YOUR LOCAL SHEDDASE| url = http://www.rndsystems.com/cb_detail_objectname_wi06_sheddase.aspx| accessdate = ] Although a single sheddase may “shed” a variety of substances, multiple sheddases can cleave the same substrate resulting in different consequences.This gene encodes and ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin.cite web | title = Entrez Gene: ADAM10 ADAM metallopeptidase domain 10| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=102| accessdate = ]

ADAM10 (EC#: 3.4.24.81) is a sheddase, and has a broad specificity for peptide hydrolysis reactions. cite web | title = Entry of ADAM10 endopeptidase (EC-Number 3.4.24.81 )| url = http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.81| accessdate = ]

tructure and Function

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. [cite journal | author=Smith KM, Cousin H, Alfandari D, White JM, DeSimone DW |title=The cysteine-rich domain regulates ADAM protease function in vivo. |journal=J. Cell Biol. |volume=159 |issue= 5 |pages= 893–902 |year= 2002 |doi=10.1083/jcb.200206023 ]

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. [cite journal | author=Wolfsberg TG, Primakoff P, Myles DG, White JM |title=ADAM, a Novel Family of Membrane Proteins Containing A Disintegrin And Metalloprotease Domain: Multipotential Functions in Cell-Cell and Cell-Matrix Interactions |journal=J. Cell Biol. |volume=131 |issue= 2 |pages= 275–8 |year= 1995 |doi=10.1083/jcb.131.2.275 ]

In the image of the active site shown above, the catalytic glutamate residue is on the left, and the zinc (light blue) is shown coordinated to three histidine residues. An inhibitor is bound to the active site, which is shown extending out of frame from the active site.

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. [cite journal | author=Lolis E, Petsko G |title=Transition-State Analogues In Protein Crystallography: Probes of the Structural Source of Enzyme Catalysis |journal=Annu. Rev. Biochem. |volume=59 |pages= 597–630 |year= 1990 |doi=10.1146/annurev.bi.59.070190.003121 ]

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. [cite journal | author=Lolis E, Petsko G |title=Transition-State Analogues In Protein Crystallography: Probes of the Structural Source of Enzyme Catalysis |journal=Annu. Rev. Biochem. |volume=59 |pages= 597–630 |year= 1990 |doi=10.1146/annurev.bi.59.070190.003121 ]

A Specific ADAM Sheddase's 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.cite web | title = 'Sheddase' helps the malaria parasite invade red blood cells| url = http://malaria.wellcome.ac.uk/doc_WTD023958.html| accessdate = ]

Recent Research

New data on the ADAM10 shedding of Ephrin/Eph complex associated with Eph on one cell surface has determined that 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.cite web | title = R&D Systems: NEED HELP AT THE CELL SURFACE? ASK YOUR LOCAL SHEDDASE| url = http://www.rndsystems.com/cb_detail_objectname_wi06_sheddase.aspx| accessdate = ] Also, in vitro studies demonstrate that 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.cite web | title = Cancer Biology & Therapy| url = http://www.ncbi.nlm.nih.gov/pubmed/16627989?dopt=Abstract| accessdate = ]

ee also

* Cluster of differentiation
*ADAM 17 Metallopeptidase
*ADAM Protein

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Wolfsberg TG, Primakoff P, Myles DG, White JM |title=ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions. |journal=J. Cell Biol. |volume=131 |issue= 2 |pages= 275–8 |year= 1995 |pmid= 7593158 |doi=
*cite journal | author=O'Bryan JP, Fridell YW, Koski R, "et al." |title=The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. |journal=J. Biol. Chem. |volume=270 |issue= 2 |pages= 551–7 |year= 1995 |pmid= 7822279 |doi=
*cite journal | author=Howard L, Lu X, Mitchell S, "et al." |title=Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types. |journal=Biochem. J. |volume=317 ( Pt 1) |issue= |pages= 45–50 |year= 1996 |pmid= 8694785 |doi=
*cite journal | author=McKie N, Edwards T, Dallas DJ, "et al." |title=Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes. |journal=Biochem. Biophys. Res. Commun. |volume=230 |issue= 2 |pages= 335–9 |year= 1997 |pmid= 9016778 |doi= 10.1006/bbrc.1996.5957
*cite journal | author=Rosendahl MS, Ko SC, Long DL, "et al." |title=Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases. |journal=J. Biol. Chem. |volume=272 |issue= 39 |pages= 24588–93 |year= 1997 |pmid= 9305925 |doi=
*cite journal | author=Yamazaki K, Mizui Y, Tanaka I |title=Radiation hybrid mapping of human ADAM10 gene to chromosome 15. |journal=Genomics |volume=45 |issue= 2 |pages= 457–9 |year= 1998 |pmid= 9344679 |doi= 10.1006/geno.1997.4910
*cite journal | author=Yamazaki K, Mizui Y, Sagane K, Tanaka I |title=Assignment of a disintegrin and metalloproteinase domain 10 (Adam10) gene to mouse chromosome 9. |journal=Genomics |volume=46 |issue= 3 |pages= 528–9 |year= 1998 |pmid= 9441766 |doi= 10.1006/geno.1997.5043
*cite journal | author=Yavari R, Adida C, Bray-Ward P, "et al." |title=Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia. |journal=Hum. Mol. Genet. |volume=7 |issue= 7 |pages= 1161–7 |year= 1999 |pmid= 9618175 |doi=
*cite journal | author=Dallas DJ, Genever PG, Patton AJ, "et al." |title=Localization of ADAM10 and Notch receptors in bone. |journal=Bone |volume=25 |issue= 1 |pages= 9–15 |year= 1999 |pmid= 10423016 |doi=
*cite journal | author=Dias Neto E, Correa RG, Verjovski-Almeida S, "et al." |title=Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 7 |pages= 3491–6 |year= 2000 |pmid= 10737800 |doi=
*cite journal | author=Hattori M, Osterfield M, Flanagan JG |title=Regulated cleavage of a contact-mediated axon repellent. |journal=Science |volume=289 |issue= 5483 |pages= 1360–5 |year= 2000 |pmid= 10958785 |doi=
*cite journal | author=Vincent B, Paitel E, Saftig P, "et al." |title=The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. |journal=J. Biol. Chem. |volume=276 |issue= 41 |pages= 37743–6 |year= 2001 |pmid= 11477090 |doi= 10.1074/jbc.M105677200
*cite journal | author=Chubinskaya S, Mikhail R, Deutsch A, Tindal MH |title=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. |journal=J. Histochem. Cytochem. |volume=49 |issue= 9 |pages= 1165–76 |year= 2001 |pmid= 11511685 |doi=
*cite journal | author=Lemjabbar H, Basbaum C |title=Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. |journal=Nat. Med. |volume=8 |issue= 1 |pages= 41–6 |year= 2002 |pmid= 11786905 |doi= 10.1038/nm0102-41
*cite journal | author=Arndt M, Lendeckel U, Röcken C, "et al." |title=Altered expression of ADAMs (A Disintegrin And Metalloproteinase) in fibrillating human atria. |journal=Circulation |volume=105 |issue= 6 |pages= 720–5 |year= 2002 |pmid= 11839628 |doi=
*cite journal | author=Colciaghi F, Borroni B, Pastorino L, "et al." |title= [alpha] -Secretase ADAM10 as well as [alpha] APPs is reduced in platelets and CSF of Alzheimer disease patients. |journal=Mol. Med. |volume=8 |issue= 2 |pages= 67–74 |year= 2002 |pmid= 12080182 |doi=
*cite journal | author=Lim R, Winteringham LN, Williams JH, "et al." |title=MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1. |journal=J. Biol. Chem. |volume=277 |issue= 43 |pages= 40997–1008 |year= 2002 |pmid= 12176995 |doi= 10.1074/jbc.M206041200
*cite journal | author=Gatta LB, Albertini A, Ravid R, Finazzi D |title=Levels of beta-secretase BACE and alpha-secretase ADAM10 mRNAs in Alzheimer hippocampus. |journal=Neuroreport |volume=13 |issue= 16 |pages= 2031–3 |year= 2003 |pmid= 12438920 |doi=
*cite journal | author=Gutwein P, Mechtersheimer S, Riedle S, "et al." |title=ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles. |journal=FASEB J. |volume=17 |issue= 2 |pages= 292–4 |year= 2003 |pmid= 12475894 |doi= 10.1096/fj.02-0430fje

PBB_Controls
update_page = yes
require_manual_inspection = no
update_protein_box = yes
update_summary = yes
update_citations = yes