Several membrane-anchored signal mediators such as cytokines (e.g. TNFα) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which, thus, has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways.

• Klíčová slova
• ADAM17, EGFR ligand release iRhom–ADAM17 complex structure, Ectodomain shedding, TNF signalling, iRhom, iRhom homology domain,
• MeSH
• buněčná membrána metabolismus   MeSH
• cytokiny metabolismus   MeSH
• membránové proteiny * metabolismus   MeSH
• modely strukturální MeSH
• protein ADAM17 metabolismus   MeSH
• transportní proteiny * genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• membránové proteiny * MeSH
• protein ADAM17 MeSH
• transportní proteiny * MeSH