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Published on: July 29, 2014
Structural basis for ADAM17 activation by the iRhom1 pseudoprotease
Joseph N Ungvary1, Joseph J Maciag1, Hala F Alnajjar1
1Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Abstract:
The a disintegrin and metalloproteinase (ADAM)-17 releases pro-inflammatory cytokines, including tumor necrosis factor-α, and several epidermal growth factor receptor ligands from cells. ADAM17 is post-translationally regulated by the inactive rhomboid pseudoproteases iRhom1 and iRhom2, and dysregulation of this signaling axis contributes to diseases ranging from chronic inflammation to cancer. Here, we present the cryo-electron microscopy structure of the ADAM17 zymogen bound to iRhom1, revealing structural features essential for complex formation and protease activation. We identify a transmembrane α-helix and conserved cytoplasmic element in iRhom1, termed the re-entry loop, that functions as a molecular relay transmitting intracellular signals across the membrane to activate ADAM17. We also demonstrate that a human disease-associated iRhom1 mutation linked to cardiomyopathy disrupts ADAM17 maturation and trafficking. Finally, we apply all-atom molecular dynamics simulations to model the mature and active ADAM17-iRhom1 complex. These findings provide mechanistic insights into how iRhom1 regulates ADAM17 function across the membrane.
Insights
The study reveals how iRhom1 regulates ADAM17 protease activity via a transmembrane molecular relay. This finding offers insights into diseases linked to ADAM17 dysregulation, such as inflammation and cancer.
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.
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