8SNM

Structure of mature human ADAM17/iRhom2 sheddase complex in complex with ADAM17 prodomain

8SNM の概要

• エントリーDOI: 10.2210/pdb8snm/pdb
• EMDBエントリー: 40629
• 分子名称: Inactive rhomboid protein 2, Disintegrin and metalloproteinase domain-containing protein 17 propeptide, Disintegrin and metalloproteinase domain-containing protein 17, ... (5 entities in total)
• 機能のキーワード: membrane protein complex, membrane protein, membrane protein-hydrolase complex, membrane protein/hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 186768.67

構造登録者

Zhao, H.,Dai, Y.,Wang, Y.,Lee, C.H. (登録日: 2023-04-27, 公開日: 2024-05-29, 最終更新日: 2024-12-11)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.84 Å)