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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity
S. Kahveci-Türköz, K. Bläsius, J. Wozniak, C. Rinkens, A. Seifert, P. Kasparek, H. Ohm, S. Oltzen, M. Nieszporek, N. Schwarz, A. Babendreyer, C. Preisinger, R. Sedlacek, A. Ludwig, S. Düsterhöft
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
DU 1582/1-1
Deutsche Forschungsgemeinschaft
Lu869/8-1
Deutsche Forschungsgemeinschaft
StUpPD_299-18
RWTH Aachen University
START#691903-06/19
Medizinische Fakultät, RWTH Aachen University
IZKF A-1-5
Medizinische Fakultät, RWTH Aachen University
RVO 68378050
Akademie Věd České Republiky
LM2018126
Ministerstvo Školství, Mládeže a Tělovýchovy
NLK
PubMed Central
od 1997
ProQuest Central
od 1997-01-01 do Před 1 rokem
Medline Complete (EBSCOhost)
od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 1997-01-01 do Před 1 rokem
- 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
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.
Institute of Molecular and Cellular Anatomy Medical Faculty RWTH Aachen University Aachen Germany
Proteomics Facility IZKF RWTH Aachen University Aachen Germany
Citace poskytuje Crossref.org
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