Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 23, Pages 16336-16348Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.557322
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Funding
- Deutsche Forschungsgemeinschaft [SFB 877, GA 2048/1-1]
- Excellence Cluster 306 Inflammation at Interfaces
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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 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-alpha, demonstrating fundamental differences in the respective shedding by ADAM17.
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