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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity
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SYSNO ASEP 0572295 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity Author(s) Kahveci-Tuerkoez, S. (DE)
Blaesius, K. (DE)
Wozniak, J. (DE)
Rinkens, C. (DE)
Seifert, A. (DE)
Kašpárek, Petr (UMG-J)
Ohm, H. (DE)
Oltzen, S. (DE)
Nieszporek, M. (DE)
Schwarz, N. (DE)
Babendreyer, A. (DE)
Preisinger, C. (DE)
Sedláček, Radislav (UMG-J) RID
Ludwig, A. (DE)
Duesterhoeft, S. (DE)Number of authors 15 Article number 135 Source Title Cellular and Molecular Life Sciences - ISSN 1420-682X
Roč. 80, č. 5 (2023)Number of pages 21 s. Language eng - English Country CH - Switzerland Keywords iRhom ; adam17 ; Ectodomain shedding ; TNF signalling ; EGFR ligand release iRhom-ADAM17 complex structure ; iRhom homology domain OECD category Biochemistry and molecular biology R&D Projects LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000978465900001 EID SCOPUS 85156136892 DOI 10.1007/s00018-023-04783-y Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://link.springer.com/article/10.1007/s00018-023-04783-y
Number of the records: 1