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

Figure 5

ADAM17 is a redox-sensitive protein. The ADAM17 membrane proximal domain (MPD), which is in close proximity to the active site, is sensitive to extracellular (or intravesicular) redox changes. This redox-sensitive ADAM17 activity is regulated by thiol-disulfide isomerization mediated by protein disulphide isomerase (PDI), an oxidoreductase sensitive to redox changes. PDI changes the disulfide bridge pattern and thus the conformation of the extracellular protease domain from an open active to a closed inactive state, by direct interaction with the membrane proximal domain (MPD), leading to the inhibition of ADAM17 proteolytic activity. Redox sensitive conformational changes likely make ADAM17 sensitive to the extracellular redox potential, which is dependent on glutathione (GSH/GSSH) and ROS.