The ADAM (A disintegrin and metalloprotease domain) family are membrane-anchored metalloproteases that mediate the proteolytic cleavage of many transmembrane proteins within their extracellular regions. This so-called ectodomain shedding plays an important role in many cell and developmental processes. ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons (Lammich et al. 1999, Kuhn et al. 2010), responsible for cleaving amyloid precursor protein (APP) in a non-amyloidogenic manner and producing APPs-alpha, a neuroprotective APP-derived peptide.
The trafficking of ADAM10 is regulated by a subgroup of the tetraspanin superfamily which have eight cysteines in the largest of the two extracellular domains and are referred to as TspanC8 tetraspanins. Tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a "tetraspanin web". Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalisation (Charrin et al. 2014). TSPAN4, 14, 15 and 33 are thought to mediate ADAM10 exit from the ER and transport to the plasma membrane in a variety of ways (Noy et al. 2016, Jouannet et al. 2016).