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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity
Open accessPreprint — published as 10.1007/s00018-023-04783-y · Paper page
Abstract
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.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Kahveci-Türköz, S., Bläsius, K., Wozniak, J., Rinkens, C., Seifert, A., Kasparek, P., Ohm, H., Oltzen, S., Nieszporek, M., Schwarz, N., Babendreyer, A., Preisinger, C., Sedlacek, R., Ludwig, A., & Düsterhöft, S.
- Affiliations
- RWTH Aachen University (DE)
- Czech Academy of Sciences Czech Centre for Phenogenomics
- Corresponding author
- Düsterhöft, Stefan
- ORCID
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2023-02-07
- Volume
- 80
- Issue
- 5
- Pages
- 135-135
- ISSN
- 1420-682X (ISSN-L)
- PMC
- PMC10148629
- OpenAlex
- W4367394761
- Cited by
- 17
- References
- 1
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 4
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cellular and Molecular Life Sciences (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (publishedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Funders
- Deutsche Forschungsgemeinschaft (DU1582/1-1, LU869/8-1)
- Ministerstvo Školství, Mládeže a Tělovýchovy (LM2018126)
- Akademie Věd České Republiky (RVO68378050, LM2018126, 68378050)
- RWTH Aachen University (StUpPD_299-18)
- Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen
- Medizinische Fakultät, RWTH Aachen University (START#691903-06/19, IZKF A-1-5)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- iRhom2, ADAM17, membrane trafficking, structure-function relationship, inflammatory processes
- MeSH terms
- ADAM17 Protein, Carrier Proteins, Cell Membrane, Membrane Proteins, Models, Structural, Cytokines
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