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

Stefan Düsterhöft1, Katharina Höbel1, Mirja Oldefest1

  • 1From the Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.

The Journal of Biological Chemistry
|May 3, 2014
PubMed

Insights

A disintegrin and metalloprotease 17 (ADAM17) utilizes its conserved stalk region, CANDIS, for IL-6 receptor binding. This interaction is regulated by the membrane-proximal domain, revealing distinct substrate shedding mechanisms.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • ADAM17 is a key sheddase regulating biological processes by cleaving substrates like IL-6R and TNF-α.
  • The extracellular region of ADAM17 includes domains crucial for its enzymatic activity and substrate interaction.

Purpose of the Study:

  • To characterize the conserved juxtamembrane stalk region of ADAM17 and its role in substrate binding.
  • To elucidate the regulatory mechanism involving the membrane-proximal domain and protein-disulfide isomerase in ADAM17 activity.
  • To identify the specific binding interface between ADAM17 and its substrate IL-6R.

Main Methods:

  • Structural and functional analysis of the ADAM17 extracellular region.
  • Investigation of protein-protein interactions between ADAM17 and its substrates.
  • Biochemical assays to determine substrate binding specificity.

Main Results:

  • The juxtamembrane stalk region of ADAM17, termed CANDIS, is conserved, α-helical, and mediates IL-6R binding.
  • ADAM17 activity is modulated by its membrane-proximal domain, acting as a molecular switch regulated by protein-disulfide isomerase.
  • The binding site on IL-6R for CANDIS was identified, highlighting specificity differences compared to TNF-α shedding.

Conclusions:

  • CANDIS is a critical functional motif in ADAM17 for IL-6R interaction.
  • The membrane-proximal domain and associated regulatory factors control ADAM17 substrate selectivity.
  • ADAM17 employs distinct mechanisms for shedding type I (IL-6R) versus type II (TNF-α) transmembrane proteins.
Keywords:
ADAMTSEnzyme InactivationInterleukinInterleukin SheddingProtein-Protein InteractionRedox RegulationTumor Necrosis Factor (TNF)

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