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Updated: Dec 25, 2025
Oral Bacterial Infection and Shedding in Drosophila melanogaster
Published on: May 31, 2018
Distance dependent shedding of IL-6R
Stefan Düsterhöft1, Anne-Kathrin Bartels2, Tomas Koudelka3
1Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Abstract:
Proteolytic processing of membrane proteins by A disintegrin and metalloprotease-17 (ADAM17) is a key regulatory step in many physiological and pathophysiological processes. This so-called shedding is essential for development, regeneration and immune defense. An uncontrolled ADAM17 activity promotes cancer development, chronic inflammation and autoimmune diseases. Consequently, the ADAM17 activity is tightly regulated. As a final trigger for the shedding event a phosphatidylserine (PS) flip to the outer leaflet of the cell membrane was recently described. PS interacts with the extracellular part of ADAM17, which results in the shedding event by shifting the catalytic domain towards the membrane close to the cleavage sites within ADAM17 substrates. Our data indicate that the intrinsic proteolytic activity of the catalytic domain is prerequisite for the shedding activity and constantly present. However, the accessibility for substrate cleavage sites is controlled on several levels. In this report, we demonstrate that the positioning of the catalytic domain towards the cleavage sites is a crucial part of the shedding process. This finding contributes to the understanding of the complex and multilayered regulation of ADAM17 at the cell surface.
Insights
A disintegrin and metalloprotease-17 (ADAM17) shedding is regulated by phosphatidylserine (PS) binding. Our findings show that catalytic domain positioning is crucial for ADAM17
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Medicine
Background:
- A disintegrin and metalloprotease-17 (ADAM17) mediates proteolytic processing (shedding) of membrane proteins.
- ADAM17 activity is vital for physiological processes but implicated in diseases like cancer and inflammation when dysregulated.
- Phosphatidylserine (PS) flip to the outer cell membrane leaflet was recently identified as a trigger for ADAM17 shedding.
Purpose of the Study:
- To investigate the regulatory mechanisms of ADAM17-mediated protein shedding.
- To elucidate the role of catalytic domain positioning in ADAM17 activity.
- To understand the interplay between PS binding and ADAM17 substrate accessibility.
Main Methods:
- Investigated the intrinsic proteolytic activity of the ADAM17 catalytic domain.
- Analyzed the effect of phosphatidylserine (PS) interaction on ADAM17 function.
- Examined the spatial positioning of the ADAM17 catalytic domain relative to substrate cleavage sites.
Main Results:
- The intrinsic proteolytic activity of the ADAM17 catalytic domain is essential and constantly present.
- Phosphatidylserine (PS) binding to ADAM17 facilitates substrate cleavage by repositioning the catalytic domain.
- The precise positioning of the catalytic domain towards cleavage sites is a critical regulatory step in ADAM17-mediated shedding.
Conclusions:
- ADAM17 activity is tightly regulated at the cell surface through multiple layers.
- Catalytic domain positioning, influenced by PS binding, is a key determinant of ADAM17 substrate accessibility and shedding.
- Understanding these regulatory mechanisms is crucial for targeting ADAM17 in disease.
