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Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis
Xue Li1,2, Thorsten Maretzky1, Jose Manuel Perez-Aguilar3,4
1Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Abstract:
A disintegrin and metalloproteinase 17 (ADAM17) controls the release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα, also known as TNF) and is crucial for protecting the skin and intestinal barrier by proteolytic activation of epidermal growth factor receptor (EGFR) ligands. The seven-membrane-spanning protein called inactive rhomboid 2 (Rhbdf2; also known as iRhom2) is required for ADAM17-dependent TNFα shedding and crosstalk with the EGFR, and a point mutation (known as sinecure, sin) in the first transmembrane domain (TMD) of Rhbdf2 (Rhbdf2sin) blocks TNFα shedding, yet little is known about the underlying mechanism. Here, we used a structure-function analysis informed by structural modeling to evaluate the interaction between the TMD of ADAM17 and the first TMD of Rhbdf2, and the role of this interaction in Rhbdf2-ADAM17-dependent shedding. Moreover, we show that double mutant mice that are homozygous for Rhbdf2 and lack Rhbdf1 closely resemble Rhbdf1/2 double knockout mice, highlighting the severe functional impact of the Rhbdf2 mutation on ADAM17 during mouse development. Taken together, these findings provide new mechanistic and conceptual insights into the critical role of the TMDs of ADAM17 and Rhbdf2 in the regulation of the ADAM17 and EGFR, and ADAM17 and TNFα signaling pathways.
Insights
The inactive rhomboid 2 (Rhbdf2) protein regulates tumor necrosis factor α (TNFα) shedding via ADAM17. A mutation in Rhbdf2
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- ADAM17 mediates shedding of TNFα and EGFR ligands, crucial for skin and intestinal barrier integrity.
- Inactive rhomboid 2 (Rhbdf2) is essential for ADAM17 activity and EGFR signaling.
- A specific Rhbdf2 mutation (sinecure, sin) impairs TNFα shedding, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which Rhbdf2 regulates ADAM17-dependent shedding.
- To investigate the interaction between the transmembrane domains (TMDs) of ADAM17 and Rhbdf2.
- To assess the functional consequences of Rhbdf2 mutations on ADAM17 and EGFR signaling.
Main Methods:
- Structure-function analysis combined with structural modeling.
- Evaluation of the interaction between ADAM17 and Rhbdf2 TMDs.
- Analysis of double mutant mice (Rhbdf2 homozygous, Rhbdf1 null).
Main Results:
- The study evaluated the interaction between ADAM17 and Rhbdf2 TMDs.
- Rhbdf2 mutation significantly impacts ADAM17 function during mouse development.
- Double mutant mice (Rhbdf2/Rhbdf1) exhibit severe developmental phenotypes.
Conclusions:
- The transmembrane domains of ADAM17 and Rhbdf2 play a critical role in regulating ADAM17 and EGFR signaling.
- Findings provide mechanistic insights into Rhbdf2-mediated control of TNFα and EGFR pathways.
- The Rhbdf2 mutation has profound effects on ADAM17 activity and downstream signaling.
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