8.A.77 The Sheddase (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.

ADAM10) is ubiquitously expressed, essential for embryonic development through activation of Notch proteins. ADAM10 regulates over 40 other transmembrane proteins and acts as a 'molecular scissor' by removing their extracellular regions. It is also a receptor for alpha-toxin, a major virulence factor of Staphylococcus aureus.

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.



This family belongs to the .

 

References:

Guo, S., M. Peng, Q. Zhao, and W. Zhang. (2012). Role of ADAM10 and ADAM17 in CD16b shedding mediated by different stimulators. Chin Med Sci J 27: 73-79.

Jowett, J.B., Y. Okada, P.J. Leedman, J.E. Curran, M.P. Johnson, E.K. Moses, H.H. Goring, S. Mochizuki, J. Blangero, L. Stone, H. Allen, C. Mitchell, and V.B. Matthews. (2012). ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α. Immunol Cell Biol 90: 966-973.

Kole, M.J., J. Qian, M.P. Waase, T.L. Klassen, T.T. Chen, G.J. Augustine, and J.L. Noebels. (2015). Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. J. Neurosci. 35: 11433-11444.

Malinin, N.L., S. Wright, P. Seubert, D. Schenk, and I. Griswold-Prenner. (2005). Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity. Proc. Natl. Acad. Sci. USA 102: 3058-3063.

Mathews, J.A., D.R. Gibb, B.H. Chen, P. Scherle, and D.H. Conrad. (2010). CD23 Sheddase A disintegrin and metalloproteinase 10 (ADAM10) is also required for CD23 sorting into B cell-derived exosomes. J. Biol. Chem. 285: 37531-37541.

Prox, J., M. Willenbrock, S. Weber, T. Lehmann, D. Schmidt-Arras, R. Schwanbeck, P. Saftig, and M. Schwake. (2012). Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10. Cell Mol Life Sci 69: 2919-2932.

Pupovac, A. and R. Sluyter. (2016). Roles of extracellular nucleotides and P2 receptors in ectodomain shedding. Cell Mol Life Sci. [Epub: Ahead of Print]

Shah, J., F. Rouaud, D. Guerrera, E. Vasileva, L.M. Popov, W.L. Kelley, E. Rubinstein, J.E. Carette, M.R. Amieva, and S. Citi. (2018). A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote α-Toxin Cytotoxicity. Cell Rep 25: 2132-2147.e7.

Vázquez, F., G. Hastings, M.A. Ortega, T.F. Lane, S. Oikemus, M. Lombardo, and M.L. Iruela-Arispe. (1999). METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J. Biol. Chem. 274: 23349-23357.

Virreira Winter, S., A. Zychlinsky, and B.W. Bardoel. (2016). Genome-wide CRISPR screen reveals novel host factors required for Staphylococcus aureus α-hemolysin-mediated toxicity. Sci Rep 6: 24242.

von Hoven, G., A.J. Rivas, C. Neukirch, S. Klein, C. Hamm, Q. Qin, M. Meyenburg, S. Füser, P. Saftig, N. Hellmann, R. Postina, and M. Husmann. (2016). Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action. Biochem. J. 473: 1929-1940.

Wewer, U.M., M. Mörgelin, P. Holck, J. Jacobsen, M.C. Lydolph, A.H. Johnsen, M. Kveiborg, and R. Albrechtsen. (2006). ADAM12 is a four-leafed clover: the excised prodomain remains bound to the mature enzyme. J. Biol. Chem. 281: 9418-9422.

Examples:

TC#NameOrganismal TypeExample
8.A.77.1.1

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

 
8.A.77.1.2

Disintegrin, 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).

Disintegrin of Homo sapiens

 
8.A.77.1.3

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

 
8.A.77.1.4

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).

Adam10 of Homo sapiens

 
8.A.77.1.5

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

 
8.A.77.1.6

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

 
8.A.77.1.7

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

 
Examples:

TC#NameOrganismal TypeExample
8.A.77.2.1

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

 
8.A.77.2.2

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)

 
Examples:

TC#NameOrganismal TypeExample