A Disintegrin and Metalloprotease 17 Dynamic Interaction Sequence,the Sweet Tooth for the Human Interleukin 6 Receptor |
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| Authors: | Stefan Düsterh?ft Katharina H?bel Mirja Oldefest Juliane Lokau Georg H Waetzig Athena Chalaris Christoph Garbers Jürgen Scheller Stefan Rose-John Inken Lorenzen Joachim Gr?tzinger |
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| Institution: | From the ‡Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.;the §CONARIS Research Institute AG, Schauenburgerstr. 116, 24118 Kiel, Germany, and ;the ¶Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany |
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| Abstract: | A disintegrin and metalloprotease 17 (ADAM17) is a major sheddase involved in the regulation of a wide range of biological processes. Key substrates of ADAM17 are the IL-6 receptor (IL-6R) and TNF-α. The extracellular region of ADAM17 consists of a prodomain, a catalytic domain, a disintegrin domain, and a membrane-proximal domain as well as a small stalk region. This study demonstrates that this juxtamembrane segment is highly conserved, α-helical, and involved in IL-6R binding. This process is regulated by the structure of the preceding membrane-proximal domain, which acts as molecular switch of ADAM17 activity operated by a protein-disulfide isomerase. Hence, we have termed the conserved stalk region “Conserved ADAM seventeen
dynamic interaction sequence” (CANDIS). Finally, we identified the region in IL-6R that binds to CANDIS. In contrast to the type I transmembrane proteins, the IL-6R, and IL-1RII, CANDIS does not bind the type II transmembrane protein TNF-α, demonstrating fundamental differences in the respective shedding by ADAM17. |
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| Keywords: | ADAMTS Enzyme Inactivation Interleukin Protein-Protein Interaction Tumor Necrosis Factor (TNF) Interleukin Shedding Redox Regulation |
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