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An arginine stretch limits ADAM10 exit from the endoplasmic reticulum
Elena Marcello1, Fabrizio Gardoni, Monica Di Luca
1Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy. elena.marcello@unimi.it
The Journal of Biological Chemistry
|January 27, 2010
Summary
Researchers identified an endoplasmic reticulum (ER) retention motif in ADAM10, a protein linked to diseases like Alzheimer's. Modifying this motif allows better cell surface transport of ADAM10.
Area of Science:
- Molecular Biology
- Cell Biology
- Neuroscience
Background:
- ADAM10 (a disintegrin and metalloproteinase 10) is crucial for shedding proteins involved in diseases such as cancer and Alzheimer Disease.
- ADAM10 requires proper trafficking for activation, making its intracellular transport a potential therapeutic target.
Purpose of the Study:
- To identify regulatory mechanisms controlling ADAM10 intracellular trafficking.
- To investigate the role of the C-terminal tail in ADAM10 ER retention and surface expression.
Main Methods:
- Site-directed mutagenesis and sequential deletion analyses of the ADAM10 C-terminal tail.
- Expression studies in heterologous cells and primary hippocampal neurons.
- Investigation of Synapse-Associated Protein 97 (SAP97) interaction with ADAM10.
Main Results:
- An arginine-rich motif (RRR) in the ADAM10 C-terminal tail was identified as an endoplasmic reticulum (ER) retention signal.
- Mutating the second arginine residue (R724A) facilitated ER exit and surface expression of ADAM10.
- Synapse-associated protein 97 (SAP97) did not enhance ER export of ADAM10, suggesting alternative regulatory pathways.
Conclusions:
- A novel ER retention motif regulating ADAM10 trafficking has been identified.
- Targeting this motif offers a potential strategy to control ADAM10 cell surface delivery and activity.
- Further research is needed to elucidate other factors governing ADAM10 ER exit.
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