Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex

• 成果类型: Article
• 署名作者: Maciag, Joseph J.; Slone, Conner E.; Alnajjar, Hala F.; Rich, Maria F.; Guion, Bryce; Ifergan, Igal; Blobel, Carl P.; Seegar, Tom C. M.
• 署名单位: University System of Ohio; University of Cincinnati; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15013
• DOI: 10.1073/pnas.2500732122
• 发表日期: 2025-06-17
• 关键词: necrosis-factor-alpha; converting-enzyme tace; tnf-alpha; substrate selectivity; rhbdf2 mutations; irhom2 controls; egf receptor; adam17; disintegrin; metalloproteinase

摘要

The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-alpha), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom)-1 and-2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17-iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.