ADAM10

Domain

The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).

Function

Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).

(Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.

Involvement in disease

Reticulate acropigmentation of Kitamura

RAK

A rare cutaneous pigmentation disorder characterized by reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet and appearing in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities. The manifestations tend to progress until middle age, after which progression of the eruptions stops. The pigmentary augmentation is found on the flexor aspects of the wrists, neck, patella and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, occasionally plantar keratoderma, and partial alopecia.

None

The disease is caused by variants affecting the gene represented in this entry.

Alzheimer disease 18

AD18

A late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Post-translational modifications

The precursor is cleaved by furin and PCSK7.

Tissue specificity

Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).

Cellular localization

• Cell membrane
• Single-pass type I membrane protein
• Golgi apparatus membrane
• Single-pass type I membrane protein
• Cytoplasmic vesicle
• Clathrin-coated vesicle
• Cell projection
• Axon
• Cell projection
• Dendrite
• Cell junction
• Adherens junction
• Cytoplasm
• Is localized in the plasma membrane but is also expressed in the Golgi apparatus and in clathrin-coated vesicles derived likely from the Golgi (PubMed:12475894). During long term depression, it is recruited to the cell membrane by DLG1 (PubMed:23676497). The immature form is mainly located near cytoplasmic fibrillar structures, while the mature form is predominantly located at zonula adherens and the cell membrane (PubMed:30463011). The localization and clustering of mature ADAM10 to zonula adherens is regulated by AFDN, TSPAN33, PLEKHA7 and PDZD11 (PubMed:30463011).

Alternative names

• Disintegrin and metalloproteinase domain-containing protein 10
• ADAM 10
• CDw156
• Kuzbanian protein homolog
• Mammalian disintegrin-metalloprotease
• ADAM10
• KUZ
• MADM

Database links

• entrezGene:102
• omim:602192
• swissprot:O14672

Target type

Proteins

Primary research area

Neuroscience

Other research areas

• Immuno-oncology
• Oncology

Molecular weight

84142Da