Structural basis for ADAM17 activation by the iRhom1 pseudoprotease.

Area of Science:

• Biochemistry
• Cell Biology
• Structural Biology

Background:

• ADAM17 protease releases cytokines and growth factor ligands, contributing to inflammation and cancer.
• ADAM17 activity is regulated by iRhom1/2, and its dysregulation is implicated in disease.

Purpose of the Study:

• To elucidate the structural mechanism of ADAM17 regulation by iRhom1.
• To understand how iRhom1 transmits signals across the membrane to activate ADAM17.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of the ADAM17-iRhom1 complex.
• Molecular dynamics (MD) simulations to model the active complex.
• Analysis of a disease-associated iRhom1 mutation.

Main Results:

• The cryo-EM structure reveals key interactions between ADAM17 zymogen and iRhom1.
• A transmembrane helix and re-entry loop in iRhom1 act as a molecular relay for signal transmission.
• A cardiomyopathy-associated iRhom1 mutation impairs ADAM17 maturation and trafficking.

Conclusions:

• iRhom1 utilizes a transmembrane re-entry loop to relay intracellular signals for ADAM17 activation.
• Structural and simulation data provide mechanistic insights into iRhom1-mediated ADAM17 regulation.
• Understanding this axis is crucial for developing therapeutics for inflammatory diseases and cancer.