adam10

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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.


      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.
      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 (EC#: 3.4.24.81) is a sheddase, and has a broad specificity for peptide hydrolysis reactions.
      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.
      In neurons, ADAM10 is the most important enzyme, with α-secretase activity for proteolytic processing of the amyloid precursor protein. 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.
      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.


      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.
      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.


      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.
      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.


      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.


      = Malaria

      =
      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.


      = Cancer

      =
      A 2020 study found that ADAM10 enhances the proliferation, migration, and invasion of osteosarcoma cells by modulating the E-cadherin/β-catenin signaling pathway, with miR-122-5p identified as a regulatory upstream target of ADAM10, suggesting that the miR-122-5p/ADAM10 axis may represent a potential therapeutic target for osteosarcoma.


      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.
      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.


      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.

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    ADAM10 - Wikipedia

    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] Members of the ADAM family are cell surface proteins with a unique structure, possessing both potential adhesion and protease domains.

    ADAM10 Gene - GeneCards | ADA10 Protein | ADA10 Antibody

    Dec 24, 2024 · ADAM10 (ADAM Metallopeptidase Domain 10) is a Protein Coding gene. Diseases associated with ADAM10 include Reticulate Acropigmentation Of Kitamura and Alzheimer Disease 18. Among its related pathways are NOTCH2 Activation and Transmission of Signal to the Nucleus and Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.

    ADAM10 ADAM metallopeptidase domain 10 [ (human)]

    Feb 8, 2025 · ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion. ADAM10-cleaved ephrin-A5 contributes to prostate cancer metastasis. Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site.

    The Role of ADAM10 in Alzheimer's Disease - PubMed

    As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides.

    ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive …

    We will discuss some examples of ADAM10 activity modulated by changing partners and subcellular compartmentalization, with the underlying hypothesis that restraining protease activity by spatial segregation is a complex and powerful regulatory tool.

    ADAM10 as a therapeutic target for cancer and inflammation

    ADAM10 is a member of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane metalloproteinases implicated in the RIPing and shedding of dozens of substrates that drive cancer progression and inflammatory disease, including Notch, E-cadherin, EGF, ErbB2 and inflammatory cytokines.

    Targeting ADAM10 in Cancer and Autoimmunity - PubMed

    Mar 24, 2020 · Generating inhibitors for A Disintegrin And Metalloproteinase 10 (ADAM10), a zinc-dependent protease, was heavily invested in by the pharmaceutical industry starting over 20 years ago.

    Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

    Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein, APP.

    The metalloproteinase ADAM10: A useful therapeutic target?

    Nov 1, 2017 · ADAM10 protease activity contributes to disorders of brain, immune system and cancer. Drugs to increase ADAM10 activity target its transcription, maturation and activation. Current ADAM10 inhibitors still lack specificity for the protease. Natural compounds can regulate the maturation and degradation of ADAM10.

    ADAM10: Possible functions in enamel development - PMC

    Nov 25, 2022 · ADAM10 may play an important role in enamel development. ADAM10 can cleave cadherins and other cell-cell junctions at specific sites where the tetraspanins have transported it and this may promote cell movement. ADAM10 can also cleave the transmembrane proteins COL17A1 and RELT.