A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

0572295 - ÚMG 2024 RIV CH eng J - Journal Article
Kahveci-Tuerkoez, S. - Blaesius, K. - Wozniak, J. - Rinkens, C. - Seifert, A. - Kašpárek, Petr - Ohm, H. - Oltzen, S. - Nieszporek, M. - Schwarz, N. - Babendreyer, A. - Preisinger, C. - Sedláček, Radislav - Ludwig, A. - Duesterhoeft, S.
A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity.
Cellular and Molecular Life Sciences. Roč. 80, č. 5 (2023), č. článku 135. ISSN 1420-682X. E-ISSN 1420-9071
R&D Projects: GA MŠMT(CZ) LM2018126
Institutional support: RVO:68378050
Keywords : iRhom * adam17 * Ectodomain shedding * TNF signalling * EGFR ligand release iRhom-ADAM17 complex structure * iRhom homology domain
OECD category: Biochemistry and molecular biology
Impact factor: 8, year: 2022
Method of publishing: Open access
https://link.springer.com/article/10.1007/s00018-023-04783-y

Several membrane-anchored signal mediators such as cytokines (e.g. TNF alpha) 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.
Permanent Link: https://hdl.handle.net/11104/0343044