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Ligand-dependent G protein coupling function of amyloid transmembrane precursor
T Okamoto1, S Takeda, Y Murayama
1Cardiovascular Research Center, Massachusetts General Hospital, Charlestown.
The Journal of Biological Chemistry
|March 3, 1995
Summary
Amyloid precursor protein (APP) acts as a receptor, specifically activating G(o) proteins. This activation is ligand-dependent and ligand-specific, revealing a novel function for APP.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- Amyloid precursor protein (APP) is known as a precursor to beta-amyloid.
- APP interacts with G(o) proteins via its cytoplasmic domain (His657-Lys676).
Purpose of the Study:
- To investigate the potential receptor function of APP.
- To determine if APP can specifically activate G(o) proteins.
Main Methods:
- Utilized phospholipid vesicles containing baculovirally produced APP695 and brain trimeric G(o).
- Employed monoclonal antibodies (22C11) against the extracellular domain of APP and synthetic peptides corresponding to APP epitopes.
- Assessed GTP gamma S binding and GTPase activity of G(o) in the presence of APP and antibodies.
Main Results:
- The antibody 22C11 increased GTP gamma S binding and GTPase turnover number of G(o) in APP/G(o) vesicles, indicating activation.
- This activation was specific to 22C11 and not observed with other antibodies or in vesicles lacking APP or containing Gi2.
- Synthetic APP66-81 (22C11 epitope) competitively inhibited 22C11's effect, and an antibody against the G(o)-binding domain of APP blocked activation.
Conclusions:
- APP exhibits a receptor function, specifically activating G(o) proteins.
- This activation is dependent on the ligand (antibody) and specific to the APP-G(o) interaction.
- APP's role extends beyond beta-amyloid precursor to include direct modulation of G(o) signaling pathways.