Figure 3.

Regulation of the ADAM metalloproteinases by phosphatidyl serine of the plasma membrane. The negatively charged membrane phospholipid phosphatidyl serine (red circles) is typically found in the inner leaflet of the membrane, but can be flipped to the outer leaflet by the action of phospholipid scramblase enzymes such as ANO6. Positively charged amino acid residues in the ADAM10 stalk domain (CANDIS) interact with negatively charged phosphatidyl serine, altering the conformation of ADAM10. These alterations are thought to bring the catalytic center of the enzyme closer to the plasma membrane and to move an inhibitory loop out of the catalytic site, thereby activating ADAM10 protease activity. PS, phosphatidyl serine; TM, transmembrane domain; CANDIS, Conserved ADAM Dynamic Interaction Sequence; MPD, membrane proximal domain; Dis, disintegrin domain; MP, metalloproteinase domain.