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.
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.