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TitleCryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals.
Journal, issue, pagesMol Cell, Vol. 84, Issue 11, Page 2152-22165.e5, Year 2024
Publish dateJun 6, 2024
AuthorsFangfang Lu / Hongtu Zhao / Yaxin Dai / Yingdi Wang / Chia-Hsueh Lee / Matthew Freeman /
PubMed AbstractA 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 ...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.
External linksMol Cell / PubMed:38781971 / PubMed Central
MethodsEM (single particle)
Resolution2.32 - 3.84 Å
Structure data

40628

8snl

EMDB-40628, PDB-8snl:
Structure of human ADAM17/iRhom2 sheddase complex
Method: EM (single particle) / Resolution: 2.78 Å

40629

8snm

EMDB-40629, PDB-8snm:
Structure of mature human ADAM17/iRhom2 sheddase complex in complex with ADAM17 prodomain
Method: EM (single particle) / Resolution: 3.84 Å

40630

8snn

EMDB-40630, PDB-8snn:
Structure of mature human ADAM17/iRhom2 sheddase complex, conformation 1
Method: EM (single particle) / Resolution: 2.32 Å

40631

8sno

EMDB-40631, PDB-8sno:
Structure of mature human ADAM17/iRhom2 sheddase complex, conformation 2
Method: EM (single particle) / Resolution: 2.78 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/HYDROLASE / Membrane protein complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex

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