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.
Highlights
A disintegrin and metalloprotease 17 (ADAM17) releases many proinflammatory mediators
Because the 14 amino acid residues directly adjacent to the membrane-proximal domain (MPD) of ADAM17 are highly conserved and do not belong to the MPD [19], we hypothesized that this segment might be important for the functionality of ADAM17
We performed ADAM17 shedding assays using extracellular alkaline phosphatase-tagged IL-1RII and TNF-␣. Shedding of both substrates by ADAM17 was reduced significantly by overexpression of PDIA6 (Fig. 6C). These results suggest that, TNF-␣ is not accessed by conserved ADAM seventeen dynamic interaction sequence (CANDIS), the protein-disulfide isomerase (PDI)-mediated structural change in the MPD of ADAM17 is sufficient to abrogate shedding by the inactivation of ADAM17
Summary
A disintegrin and metalloprotease 17 (ADAM17) releases many proinflammatory mediators. Results: The conserved ADAM seventeen dynamic interaction sequence (CANDIS) mediates effective substrate binding and is controlled by the disulfide-regulated conformation of the preceding membrane-proximal domain (MPD). This study demonstrates that this juxtamembrane segment is highly conserved, ␣-helical, and involved in IL-6R binding This process is regulated by the structure of the preceding membraneproximal domain, which acts as molecular switch of ADAM17 activity operated by a protein-disulfide isomerase. The type I transmembrane protein a disintegrin and metalloprotease 17 (ADAM17) is a key protease that is involved in the regulation of a wide variety of biological processes. We show that binding of the IL-6R, but not TNF-␣, which are both key ADAM17 substrates, is mediated by this small ␣-helical juxtamembrane segment, which we termed “conserved ADAM seventeen dynamic interaction sequence” (CANDIS). We demonstrate that the substrate binding property of CANDIS is modulated by the MPD, which is switched by PDI
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