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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

Selcan Kahveci-Türköz1, Katharina Bläsius1, Justyna Wozniak1

  • 1Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.

Cellular and Molecular Life Sciences : CMLS
|April 29, 2023
PubMed

Insights

Artificial intelligence modeling revealed key regions within the iRhom homology domain (IRHD) that regulate the iRhom-ADAM17 complex. This finding advances understanding of cell surface protein shedding in inflammation and development.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Structural Biology

Background:

  • ADAM17 metalloproteinase sheds cell surface proteins like TNFα, crucial for inflammation and development.
  • iRhom1 and iRhom2 proteins are essential for ADAM17 trafficking and regulation.
  • The structural basis of the iRhom-ADAM17 complex remains largely unknown.

Purpose of the Study:

  • To elucidate the structure-function relationship of the iRhom-ADAM17 complex using AI-based modeling.
  • To identify specific functional regions within the iRhom homology domain (IRHD).

Main Methods:

  • AI-based computational modeling to predict complex structure.
  • In vitro, ex vivo, and in vivo experimental validation.
  • Analysis of iRhom homology domain (IRHD) function.

Main Results:

  • AI modeling identified distinct IRHD regions critical for iRhom function.
  • Experimental approaches confirmed the predicted structure-function determinants.
  • The IRHD plays a regulatory role in iRhom-ADAM17 complex stability and trafficking.

Conclusions:

  • Mechanistic insights into iRhom-ADAM17 complex regulation and function.
  • Understanding the role of IRHD in controlling ADAM17-mediated shedding.
  • Implications for inflammatory and developmental signaling pathways.
Keywords:
ADAM17EGFR ligand release iRhom–ADAM17 complex structureEctodomain sheddingTNF signallingiRhomiRhom homology domain

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