ADAMs and protein disulfide isomerase: the key to regulated cell-surface protein ectodomain shedding?
The ADAM disintegrin metalloproteinases (where ADAM is 'a disintegrin and metalloproteinase') are a family of transmembrane cell-surface proteins with essential roles in adhesion and proteolytic processing in all animals. The archetypal family member is ADAM17 {also known as TACE [TNFalpha (tumour necrosis factor alpha)-converting enzyme]}, which is involved in processing pro-TNFalpha and in the activation of ligands for the EGFR [EGF (epidermal growth factor) receptor], as well as cleavage of diverse cell-surface receptors and adhesion molecules. ADAM-mediated shedding is itself influenced via cell signalling pathways. In this issue of the Biochemical Journal, Willems et al. make the observation that phorbol ester activates shedding by ADAM17 by affecting the activity of PDI (protein disulfide isomerase). They propose that PDI maintains ADAM17 in an inactive 'closed' state and PMA stimulation generates ROS (reactive oxygen species) and thus an altered redox environment, which in turn inactivates PDI and allows ADAM17 to adopt an 'open' active conformation. This activation is accompanied by changes in disulfide bonds in the ADAM17 ectodomain. This is a novel and exciting finding that could help to unlock the actions of ADAM sheddases, as well as a host of other mechanisms that rely upon rapid alterations in protein conformation on the cell surface.
Bass
Rosemary
R
Cellular Protease Group, School of Biological Sciences, University of East Anglia, Norwich NR47TJ, UK.
Edwards
Dylan R
DR
D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D019704:Protein Disulfide-Isomerases