8.A.77 The Sheddase or ADAM (Sheddase) Family
Ectodomain shedding of integral membrane receptors, channels and transporters results in the release of soluble molecules and
modification of the transmembrane portions of the substrate proteins to mediate or modulate extracellular and intracellular
signalling. Ectodomain shedding is stimulated by a variety of mechanisms, including the activation
of P2 receptors by extracellular nucleotides. Metalloproteinases play the primary role in the shedding of various cell surface molecules
including amyloid precursor protein, CD23, CD62L, and members of the epidermal growth factor,
immunoglobulin and tumour necrosis factor families. Pupovac and Sluyter 2016 discuss the mechanisms involved in
shedding, demonstrating central roles for the P2 receptors, P2X7 (TC# 1.A.7.1.3) and P2Y2 (TC# 9.A.14.13.16), and
the sheddases, ADAM10 and ADAM17, in this process.
'A disintegrin and metalloproteases' (ADAMs) family serves diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. Other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, while others are expressed tissue specifically. In the mammalian nervous system, non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. ADAM10 has additional substrates, and its substrate selectivity may be regulated by tetraspanins. ADAM8 and ADAM17 are involved in neuroinflammation, while ADAM17 additionally regulates neurite outgrowth and myelination, and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD (Hsia et al. 2019).
ADAM10 is ubiquitously expressed and essential for embryonic development through activation of Notch proteins (Saftig and Lichtenthaler 2015). ADAM10 regulates over 40 other transmembrane proteins and acts as a 'molecular scissor' by removing their extracellular regions (Matthews et al. 2017). It is also a receptor for alpha-toxin, a major virulence factor of Staphylococcus aureus (Shah et al. 2018). Levels of the transmembrane ADAM9 and ADAM18 at the cell surface are regulated by sorting nexin9 (SNX9) (Mygind et al. 2018).
The ADAM11 protein (8.A.77.2.1) is an auxilary protein responsible for the localization of Kv1.1 and Kv1.2 K+ channel subunit complexes to the distal terminai of certain nerve cells (Kole et al. 2015). Direct interaction with Kv1 channel proteins has been demonstrated.
References:
ADAM11 of 769 aas and 2 TMSs, N- and C-terminal. Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. ADAM11 is essential for proper localization of Kv1.1 and Kv1.2 K+ channel subunit complexes to the distal tubule plasma membrane. It is the first Kv1 interacting protein to be discovered (Kole et al. 2015). It has four domains recognized by CDD: Pep-M12B - Proopep - ZnMc/Reprolysin - Disintegrin.
ADAM11 of Homo sapiens
Disintegrin and metalloproteinase domain-containing protein 15, ADAM15 or MDC15, a member of the of 863 aas and 2 TMSs, one N-terminal and the other near the C-terminus of the protein. It is an active metalloproteinase with gelatinolytic and collagenolytic activity, and it plays a role in the wound healing process. It mediates both heterotypic intraepithelial cell/T-cell interactions and homotypic T-cell aggregation. It also inhibits beta-1 integrin-mediated cell adhesion and migration of airway smooth muscle cells (Martin et al. 2002; Charrier et al. 2005; Böhm et al. 2005). Membrane proteins regulated by ADAM15 have been identified using SUSPECS proteomics (Calligaris et al. 2023).
ADAM15 of Homo sapiens
Disintegrin or ADAM17, a metaloprotease (sheddase) of 824 aas and 2 TMSs near the protein's N- and C-termini. Sheds many membrane-bound proteins, especially receptors, with a preference for acidic amino acids at the P1' position. Cleaves membrane proteins and modifies their activities while releasing the proteotytic products into the external medium (Pupovac and Sluyter 2016). ANO6 (TC# 1.A.17.1.4), by virtue of its scramblase activity, may play a role as a regulator of the ADAM-network in the plasma membrane. It is responsible for the proteolytic release of several cell-surface proteins, including the p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (Thathiah et al. 2003). It acts as an activator of the Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (Boskovski et al. 2013). Blocking ADAM17 as an immune modulator together with appropriate antibiotics provides a therapeutic avenue for sepsis treatment (Mishra et al. 2020). ADAM17 in the proximal kidney tubule impacts on glomerular inflammation and fibrosis (Palau et al. 2021). An ADAM17 selective inhibitor promotes glucose uptake by activating AMPK (Toma et al. 2024).
Disintegrin of Homo sapiens
Metalloproteinase of 775 aas and 2 TMSs, N- and C-terminal, Adam28. Epididymal metalloproteinase-like, disintegrin-like, and cysteine-rich protein II. May function in ectodomain shedding of lymphocyte surface target proteins such as FASL and CD40L. May also be involved in sperm maturation (Jowett et al. 2012).
Adam28 of Homo sapiens
Adam10 of 748 aas and 2 TMSs, an N- and a C-terminal TMS (Prox et al. 2012). Both ADAM10 and ADAM17 shed CD16b (Guo et al. 2012) and CD23 (Mathews et al. 2010). By destroying cell-cell contacts through cleavage of cadherins, the metalloproteinase ADAM10 (a disintegrin and metalloproteinase 10) critically contributes to α-toxin-dependent pathology of experimental S. aureus infections in mice. ADAM10 is a receptor for α-toxin (von Hoven et al. 2016; Virreira Winter et al. 2016). ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C-terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. ADAM10 is locked at junctions through binding of its cytoplasmic C-terminus to afadin. Junctionally clustered ADAM10 supports the efficient formation of stable toxin pores. Instead, disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 and toxin junctional clustering. This promotes toxin pore removal from the cell surface through an actin- and macropinocytosis-dependent process, resulting in cell recovery from initial injury and survival (Shah et al. 2018). Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells (Caolo et al. 2020). How the function of ADAM10 is regulated by tetraspanins, and how ADAM10 may promote enamel formation has been discussed (Shahid et al. 2022). Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis (Drexhage et al. 2024). Regulation of ADAM10 activity may occur through microdomain-dependent intracellular calcium changes (Gharzia et al. 2024). At pH 7.5, both protomers in the dimer adopt an outward-facing (OF) conformation, with Zn2+ ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn2+ exhibits various conformations [OF/OF, OF/IF (inward-facing), and IF/IF] (Long et al. 2024).
Adam10 of Homo sapiens
ADAM12 of 909 aas and 2 TMSs, N- and C-terminal. Involved in procession amyloid-beta (TC#1.C.50) (Malinin et al. 2005). Also involved in skeletal muscle regeneration, specifically at the onset of cell fusion, and in macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors. It is a four-leafed clover: the excised prodomain remains bound to the mature enzyme (Wewer et al. 2006).
ADAM12 of Homo sapiens
Ats1 or ADAMTS1 of 967 aas. A disintegrin and metalloprotease with thrombospondin motifs 1. Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. Has angiogenic inhibitory activity that may be associated with various inflammatory processes as well as development of cancer cachexia (Vázquez et al. 1999).
Ats1 of Homo sapiens
A disintegrin and metalloproteinase with thrombospondin motifs 4, ADAMTS4, of 837 aas and 2 TMSs, one N-terminal, and one near the C-terminus. Cleaves aggrecan, a cartilage proteoglycan. May play a role in the
destruction of aggrecan in arthritic diseases. Could also be a critical
factor in the exacerbation of neurodegeneration in Alzheimer disease. Its synthesis is regulated by Aqp1 (TC# 1.A.8.8.1).
ADAMTS4 of Homo sapiens
Papilin isoform X5 of 3072 aas. This large protein contains three domains that with filters, has an N-terminal domain that hits proteases of TC family 8.A.77 with a minimal e-value of e-51, a large domain in the C-terminal half of the protein that hits proteases of TC family 8.A.13 with a minimal e-value of e-20, and a small C-terminal domain that hits protein of TC family 8.A.23 with a minimal e-value of e-13. Numerous papilins come up in BLAST searches using 1.B.89.1.1 (an outer membrane porin from Actinobacteria) with low scores. between residues 1762 and 2518, there are about 12 repeats of ~60 aas. They are homologous to the amyloid A4 protein (TC# 1.C.50.1.1).
Papilin of Helicoverpa armigera
Metalopeptidase (sheddase), Meprin A, MEP1B of 701 aas and 2 TMSs, N- and C-terminal. It has three domains, N-terminal: ZnMc metal protease; Middle: MAM extracellular receptor domain, and C-terminal: MATH domain (see CDD). Proteolyzed and sheds many membrane-bound proteins. Shows a preference for acidic amino acids at the P1' position. Cleaves membrane proteins and modifies their activities while releasing the proteotytic products into the external medium (Pupovac and Sluyter 2016).
Meprin A of Homo sapiens
Astacin-like metalloprotease precursor of 261 aas; corresponds to the N-terminal domain of 8.A.77.2.1.
Metalloprotease of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)
Uncharacterized protein LOC67715 isoform 2 precursor of 269 aas. The anti-aging protein (TC# 8.A.77.2.3) contributes to proton-induced aging via the NCX1-pathway (Osanai et al. 2018). .
UP of Mus musculus
Bowman-Birk type proteinase inhibitor DE-3 of 76 aas. It is a serine protease inhibitor.
DE-3 of Macrotyloma axillare