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Cited by 17Protease and Inhibitor MechanismsCell death mechanisms and regulationCellular transport and secretion

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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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Kahveci-Türköz, Selcan, Bläsius, Katharina, Wozniak, Justyna, Rinkens, Cindy, Seifert, Anke, Kasparek, Petr, Ohm, Henrike, Oltzen, Shixin, Nieszporek, Martin, Schwarz, Nicole, Babendreyer, Aaron, Preisinger, Christian, Sedlacek, Radislav, Ludwig, Andreas, Düsterhöft, Stefan·2023·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-023-04783-yPMC PMC10148629

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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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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)
Corresponding author
Düsterhöft, Stefan
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2023-04-29
Volume
80
Issue
5
Pages
135-135
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-023-04783-y
PMC
PMC10148629
OpenAlex
W4367394761
Cited by
17
References
6
Citations by year
2026: 4 · 2025: 4 · 2024: 5 · 2023: 4
FWCI
2.17
Type
journal article
Language
en
Open access
Licence
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 (DU 1582/1-1, Lu869/8-1)
  • RWTH Aachen University (StUpPD_299-18)
  • Medizinische Fakultät, RWTH Aachen University (START#691903-06/19, IZKF A-1-5)
  • Akademie Věd České Republiky (RVO 68378050)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LM2018126)
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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