A Disintegrin and Metalloprotease 17 Dynamic Interaction Sequence, the Sweet Tooth for the Human Interleukin 6 Receptor

作者：Duesterhoeft Stefan; Hoebel Katharina; Oldefest Mirja; Lokau Juliane; Waetzig Georg H; Chalaris Athena; Garbers Christoph; Scheller Juergen; Rose John Stefan; Lorenzen Inken; Groetzinger Joachim

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(23): 16336-16348.

DOI：10.1074/jbc.M114.557322

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-alpha. 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, alpha-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 %26quot;Conserved ADAM seventeen dynamic interaction sequence%26quot; (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-alpha, demonstrating fundamental differences in the respective shedding by ADAM17.

• 出版日期2014-6-6