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  11. Structural Insights Into The Activation And Inhibition Of The Adam17-irhom2 Complex

Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex

Joseph J Maciag1, Conner E Slone1, Hala F Alnajjar1

  • 1Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267.

Proceedings of the National Academy of Sciences of the United States of America
|June 13, 2025

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View abstract on PubMed

Summary
This summary is machine-generated.

Researchers reveal the cryo-EM structure of ADAM17 bound to iRhom2, detailing how this complex regulates enzyme activity. These findings illuminate therapeutic targets for diseases linked to dysregulated ADAM17 (a disintegrin and metalloproteinase)-17.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Medicine

Background:

  • ADAM17 (a disintegrin and metalloproteinase)-17 is a key enzyme regulating EGFR ligands and TNF-α, crucial for development and immunity.
  • Dysregulated ADAM17 activity is implicated in cancer, inflammation, and viral infections like SARS-CoV-2.
  • ADAM17 zymogen maturation and activity are controlled by binding partners, inactive rhomboid proteins (iRhom)-1 and -2.

Purpose of the Study:

  • To determine the cryo-EM structure of the ADAM17 zymogen in complex with iRhom2.
  • To elucidate the molecular interactions governing ADAM17-iRhom2 complex formation and regulation.
  • To identify mechanisms of inhibition by therapeutic antibodies and the ADAM17 prodomain.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to resolve the structure of the ADAM17-iRhom2 complex.
Keywords:
ADAM17ectodomain sheddingiRhom2immunity

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  • Biochemical assays to analyze protein interactions and enzyme activity.
  • Cellular assays to validate structural findings and functional implications.

    • Main Results:

    • The cryo-EM structure of the ADAM17 zymogen bound to iRhom2 was determined.
    • Key interactions within the complex were elucidated, including the inhibitory role of the ADAM17 prodomain and MEDI3622 antibody.
    • A novel function of an iRhom2 cytoplasmic loop in ADAM17 activation was uncovered.

    Conclusions:

    • Structural insights into the ADAM17-iRhom2 complex provide a mechanistic understanding of its regulation.
    • The findings reveal potential therapeutic strategies targeting the ADAM17 complex for various diseases.
    • Validation through cellular assays supports the functional relevance of the observed interactions.