ADAM10
Ensembl | |||||||||
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RefSeq (protein) | |||||||||
Location (UCSC) | Chr 15: 58.59 – 58.75 Mb | Chr 9: 70.59 – 70.69 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
ADAM10 endopeptidase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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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.[5]
Function
Members of the
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.[5]
ADAM10 (EC#: 3.4.24.81) is a sheddase, and has a broad specificity for peptide hydrolysis reactions.[9]
ADAM10 cleaves
In
ADAM10 belongs to subfamily A, the most ancestral subfamily of ADAM proteins, which is shared by all major groups of
Structure
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.[14]
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.[15]
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.[16]
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.[16]
Clinical significance
Brain diseases
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.[17]
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.[18]
Breast cancer
In combination with low doses of
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.[20]
See also
- Cluster of differentiation
- ADAM 17 Metallopeptidase
- ADAM Protein
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137845 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000054693 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: ADAM10 ADAM metallopeptidase domain 10".
- PMID 15182168.
- S2CID 9009213.
- S2CID 7011302.
- ^ "Entry of ADAM10 endopeptidase (EC-Number 3.4.24.81 )".
- S2CID 7962666.
- PMID 22553493.
- PMID 32635934.
- S2CID 218832838.
- PMID 12460986.
- PMID 7593158.
- ^ PMID 2197984.
- S2CID 46800368.
- ^ "'Sheddase' helps the malaria parasite invade red blood cells". Archived from the original on 2008-04-12.
- S2CID 23463401.
- PMID 23676497.
Further reading
- 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. PMID 7593158.
- O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET (January 1995). "The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage". The Journal of Biological Chemistry. 270 (2): 551–7. S2CID 46190313.
- Howard L, Lu X, Mitchell S, Griffiths S, Glynn P (July 1996). "Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types". The Biochemical Journal. 317 ( Pt 1) (1): 45–50. PMID 8694785.
- McKie N, Edwards T, Dallas DJ, Houghton A, Stringer B, Graham R, et al. (January 1997). "Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes". Biochemical and Biophysical Research Communications. 230 (2): 335–9. PMID 9016778.
- Rosendahl MS, Ko SC, Long DL, Brewer MT, Rosenzweig B, Hedl E, et al. (September 1997). "Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases". The Journal of Biological Chemistry. 272 (39): 24588–93. S2CID 21399815.
- Yamazaki K, Mizui Y, Tanaka I (October 1997). "Radiation hybrid mapping of human ADAM10 gene to chromosome 15". Genomics. 45 (2): 457–9. PMID 9344679.
- Yamazaki K, Mizui Y, Sagane K, Tanaka I (December 1997). "Assignment of a disintegrin and metalloproteinase domain 10 (Adam10) gene to mouse chromosome 9". Genomics. 46 (3): 528–9. PMID 9441766.
- Yavari R, Adida C, Bray-Ward P, Brines M, Xu T (July 1998). "Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia". Human Molecular Genetics. 7 (7): 1161–7. PMID 9618175.
- Dallas DJ, Genever PG, Patton AJ, Millichip MI, McKie N, Skerry TM (July 1999). "Localization of ADAM10 and Notch receptors in bone". Bone. 25 (1): 9–15. PMID 10423016.
- Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, et al. (March 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. PMID 10737800.
- Hattori M, Osterfield M, Flanagan JG (August 2000). "Regulated cleavage of a contact-mediated axon repellent". Science. 289 (5483): 1360–5. PMID 10958785.
- Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D, De Strooper B, et al. (October 2001). "The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein". The Journal of Biological Chemistry. 276 (41): 37743–6. PMID 11477090.
- Chubinskaya S, Mikhail R, Deutsch A, Tindal MH (September 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". The Journal of Histochemistry and Cytochemistry. 49 (9): 1165–76. S2CID 6879742.
- Lemjabbar H, Basbaum C (January 2002). "Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells". Nature Medicine. 8 (1): 41–6. S2CID 7135441.
- Healy EF, Romano P, Mejia M, Lindfors G (November 2010). "Acetylenic inhibitors of ADAM10 and ADAM17: in silico analysis of potency and selectivity". Journal of Molecular Graphics & Modelling. 29 (3): 436–42. PMID 20863729.
- Arndt M, Lendeckel U, Röcken C, Nepple K, Wolke C, Spiess A, et al. (February 2002). "Altered expression of ADAMs (A Disintegrin And Metalloproteinase) in fibrillating human atria". Circulation. 105 (6): 720–5. S2CID 10279346.
- Colciaghi F, Borroni B, Pastorino L, Marcello E, Zimmermann M, Cattabeni F, et al. (February 2002). "[alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients". Molecular Medicine. 8 (2): 67–74. PMID 12080182.
- Lim R, Winteringham LN, Williams JH, McCulloch RK, Ingley E, Tiao JY, et al. (October 2002). "MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1" (PDF). The Journal of Biological Chemistry. 277 (43): 40997–1008. S2CID 40077371.
- Gatta LB, Albertini A, Ravid R, Finazzi D (November 2002). "Levels of beta-secretase BACE and alpha-secretase ADAM10 mRNAs in Alzheimer hippocampus". NeuroReport. 13 (16): 2031–3. PMID 12438920.
- Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Gast D, Joumaa S, et al. (February 2003). "ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles". FASEB Journal. 17 (2): 292–4. S2CID 21521110.
External links
- ADAM10 human gene location in the UCSC Genome Browser.
- ADAM10 human gene details in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: O14672 (Disintegrin and metalloproteinase domain-containing protein 10) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.