8SNN

Structure of mature human ADAM17/iRhom2 sheddase complex, conformation 1

Summary for 8SNN

• Entry DOI: 10.2210/pdb8snn/pdb
• EMDB information: 40630
• Descriptor: Disintegrin and metalloproteinase domain-containing protein 17, Inactive rhomboid protein 2, CALCIUM ION (3 entities in total)
• Functional Keywords: membrane protein complex, membrane protein, membrane protein-hydrolase complex, membrane protein/hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 161845.98

Authors

Zhao, H.,Dai, Y.,Wang, Y.,Lee, C.H. (deposition date: 2023-04-27, release date: 2024-05-29, Last modification date: 2024-12-11)

Primary citation

Lu, F.,Zhao, H.,Dai, Y.,Wang, Y.,Lee, C.H.,Freeman, M.
Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals.
Mol.Cell, 84:2152-2165.e5, 2024

PubMed Abstract: A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis factor (TNF) and cancer-implicated epidermal growth factor (EGF) family growth factors. iRhom2, a rhomboid-like, membrane-embedded pseudoprotease, is an essential cofactor of ADAM17. Here, we present cryoelectron microscopy (cryo-EM) structures of the human ADAM17/iRhom2 complex in both inactive and active states. These reveal three regulatory mechanisms. First, exploiting the rhomboid-like hallmark of TMD recognition, iRhom2 interacts with the ADAM17 TMD to promote ADAM17 trafficking and enzyme maturation. Second, a unique iRhom2 extracellular domain unexpectedly retains the cleaved ADAM17 inhibitory prodomain, safeguarding against premature activation and dysregulated proteolysis. Finally, loss of the prodomain from the complex mobilizes the ADAM17 protease domain, contributing to its ability to engage substrates. Our results reveal how a rhomboid-like pseudoprotease has been repurposed during evolution to regulate a potent membrane-tethered enzyme, ADAM17, ensuring the fidelity of inflammatory and growth factor signaling.

PubMed: 38781971
DOI: 10.1016/j.molcel.2024.04.025

Experimental method

ELECTRON MICROSCOPY (2.32 Å)