ADAM10

ADAM10
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1M1I
Identifiers
Aliases	ADAM10, AD10, AD18, CD156c, HsT18717, MADM, RAK, kuz, CDw156, ADAM metallopeptidase domain 10
External IDs	OMIM: 602192 MGI: 109548 HomoloGene: 865 GeneCards: ADAM10
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q21.3 Start 58,588,809 bp[1] End 58,749,791 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 D|9 39.53 cM Start 70,678,997 bp[2] End 70,780,229 bp[2]
RNA expression pattern Bgee Top expressed in testicle brain ovary prosencephalon kidney colon corpus callosum endometrium More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity SH3 domain binding endopeptidase activity metal ion binding integrin binding peptidase activity GO:0001948 protein binding signaling receptor binding hydrolase activity protein kinase binding metallopeptidase activity metalloendopeptidase activity Cellular component cytoplasm integral component of membrane membrane GO:0097483, GO:0097481 postsynaptic density focal adhesion plasma membrane perinuclear endoplasmic reticulum Golgi-associated vesicle tetraspanin-enriched microdomain extracellular exosome nucleus cell surface Golgi membrane extracellular space Golgi apparatus specific granule membrane tertiary granule membrane endoplasmic reticulum lumen trans-Golgi network synaptic vesicle dendrite neuronal cell body dendritic spine postsynaptic membrane postsynapse glutamatergic synapse Biological process Notch signaling pathway positive regulation of cell migration ephrin receptor signaling pathway cell-cell signaling constitutive protein ectodomain proteolysis protein processing extracellular matrix disassembly in utero embryonic development proteolysis monocyte activation response to tumor necrosis factor protein phosphorylation positive regulation of cell growth positive regulation of T cell chemotaxis positive regulation of cell population proliferation Notch receptor processing integrin-mediated signaling pathway membrane protein ectodomain proteolysis negative regulation of cell adhesion neutrophil degranulation post-translational protein modification cellular protein metabolic process spermatogenesis amyloid-beta formation Notch receptor processing, ligand-dependent positive regulation of apoptotic process regulation of dendritic spine morphogenesis response to antineoplastic agent regulation of neurotransmitter receptor localization to postsynaptic specialization membrane postsynapse organization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	102	11487
Ensembl	ENSG00000137845	ENSMUSG00000054693
UniProt	O14672	O35598
RefSeq (mRNA)	NM_001110 NM_001320570	NM_007399
RefSeq (protein)	NP_001101 NP_001307499 NP_001101.1	NP_031425
Location (UCSC)	Chr 15: 58.59 – 58.75 Mb	Chr 9: 70.68 – 70.78 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 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.^[6][7][8]

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 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.^[10]

In neurons, ADAM10 is the most important enzyme, with α-secretase activity for proteolytic processing of the amyloid precursor protein.^[11] 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.^[12]

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.^[13]

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 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.^[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 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.^[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 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.^[19]

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[]

Further reading[]

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.