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

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• 作者：Stefan D眉sterh枚ft ; Sascha Jung ; Chien-Wen Hung ; Andreas Tholey ; Frank D. S枚nnichsen ; Joachim Gr枚tzinger ; Inken Lorenzen
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：April 17, 2013
• 年：2013
• 卷：135
• 期：15
• 页码：5776-5781
• 全文大小：319K
• 年卷期：v.135,no.15(April 17, 2013)
• ISSN：1520-5126

文摘

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.