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Published on: April 3, 2014
Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains
Abstract:
Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It has been shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer's disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. As several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified as present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.
Insights
Tetraspanin 8 (TSPAN8) interacts with meprin β, an enzyme implicated in Alzheimer's disease. While TSPAN8 doesn't alter meprin β activity, it may influence its cell surface localization and proteolytic functions.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Meprin β is a cell surface ectodomain sheddase involved in Alzheimer's disease pathogenesis through amyloid precursor protein (APP) cleavage.
- Tetraspanins are known to modulate metalloprotease activity and localization.
Purpose of the Study:
- To identify non-proteolytic regulators of meprin β.
- To investigate the interaction between meprin β and tetraspanin 8 (TSPAN8).
Main Methods:
- Split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library.
- Cell biological methods to confirm protein interactions.
- Analysis of meprin β catalytic activity and APP cleavage.
- Identification of protein localization in tetraspanin-enriched microdomains.
Main Results:
- Tetraspanin 8 (TSPAN8) was identified as an interaction partner of meprin β.
- Direct binding between TSPAN8 and meprin β was confirmed.
- TSPAN8 did not affect meprin β's catalytic activity or APP cleavage.
- Both meprin β and TSPAN8 were found in tetraspanin-enriched microdomains.
Conclusions:
- TSPAN8 interacts with meprin β but does not modulate its enzymatic activity or substrate cleavage.
- TSPAN8 may play a role in the cell surface organization of meprin β.
- Further research is needed to identify the specific proteolytic processes influenced by TSPAN8-meprin β interactions.
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