Membrane-Proximal Domain of a Disintegrin and Metalloprotease-17 Represents the Putative Molecular Switch of Its Shedding Activity Operated by Protein-disulfide Isomerase

Citations Over TimeTop 10% of 2013 papers

Abstract

A disintegrin and metalloprotease-17 (ADAM17) is a major sheddase responsible for the regulation of a wide range of biological processes, like cellular differentiation, regeneration, or cancer progression. Hitherto, the mechanism regulating the enzymatic activity of ADAM17 is poorly understood. Recently, protein-disulfide isomerase (PDI) was shown to interact with ADAM17 and to down-regulate its enzymatic activity. Here we demonstrate by NMR spectroscopy and tandem-mass spectrometry that PDI directly interacts with the membrane-proximal domain (MPD), a domain of ADAM17 involved in its dimerization and substrate recognition. PDI catalyzes an isomerization of disulfide bridges within the thioredoxin motif C600XXC603 of the MPD and results in a drastic structural change between an active open state and an inactive closed conformation. This conformational change of the MPD putatively acts as a molecular switch, facilitating a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity.

Related Papers

• → Structural Characterization of the Ectodomain of a Disintegrin and Metalloproteinase-22 (ADAM22), a Neural Adhesion Receptor Instead of Metalloproteinase(2009)65 cited
• → A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems(2016)63 cited
• → Molecular cloning and functional characterization of a snake venom metalloprotease(1999)47 cited
• → Functional roles of the two distinct domains of halysase, a snake venom metalloprotease, to inhibit human platelet aggregation(2005)23 cited
• The Role of CD9 in Regulating TNF-α-Induced Expression of A Disintegrin and Metalloprotease 17 (ADAM17) in Aortic Endothelial Cells(2019)