A disintegrin and metalloprotease 17 dynamic interaction sequence, the sweet tooth for the human interleukin 6 receptor.

Authors:
Stefan Düsterhöft, Katharina Höbel, Mirja Oldefest, Juliane Lokau, Georg H Waetzig, Athena Chalaris, Christoph Garbers, Jürgen Scheller, Stefan Rose-John, Inken Lorenzen, Joachim Grötzinger
Year of publication:
2014
Volume:
289
Issue:
23
Issn:
0021-9258
Journal title abbreviated:
J BIOL CHEM
Journal title long:
JBC papers in press
Impact factor:
4.238
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.