BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production.
Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid beta (Abeta) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648-719 of APP751 and 46-106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as beta-secretase-generated COOH-terminal fragments while decreasing the levels of alpha-secretase-generated COOH-terminal fragments as well as the secretion of total APP and Abeta peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders.
Fotinopoulou
Angeliki
A
Division of Animal & Human Physiology, Department of Biology, National & Kapodistrian University of Athens, 157 84 Panepistimiopolis, Ilisia, Athens, Greece.
Tsachaki
Maria
M
Vlavaki
Maria
M
Poulopoulos
Alexandros
A
Rostagno
Agueda
A
Frangione
Blas
B
Ghiso
Jorge
J
Efthimiopoulos
Spiros
S
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms