The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Figure 2

ADAM17 domain structure. ADAM17 is an atypical member of the ADAM family. It has additional disulfide bonds in the metalloprotease domain, and it lacks two calcium binding sites in the disintegrin domain. The membrane proximal domain (MPD), replacing the cysteine-rich and EGF-like domains, with a novel alpha/beta fold has a shorter cysteine-rich segment. The MPD has cysteine residues determining the ADAM17 conformation (open/closed) and ADAM17 protease activity (active/inactive switch). The MPD is in close proximity to the active site likely due to a C-shaped conformation of the extracellular part of mature ADAM17 [99]. ADAM17 lacks an EGF-like domain, so the MPD is followed by the juxtamembrane region “conserved ADAM17 dynamic interaction sequence” (CANDIS) involved in substrate recognition [162]. The trans-membrane region ends with a cytoplasmic tail with phosphorylation sites, which are likely important for ADAM17 activity and trafficking [97–101].