Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles.
Processing of the amyloid-β (Aβ) precursor protein (APP) has been extensively studied since it leads to production of Aβ peptides. Toxic forms of Aβ aggregates are considered the cause of Alzheimer's disease (AD). On the other end, BRI2 is implicated in APP processing and Aβ production. We have investigated the precise mechanism by which BRI2 modulates APP cleavages and have found that BRI2 forms a mature BRI2 polypeptide that is transported to the plasma membrane and endosomes where it interacts with mature APP. Notably, immature forms of APP and BRI2 fail to interact. Mature BRI2 inhibits APP processing by α-, β- and γ-secretases on the plasma membrane and in endocytic compartments. Thus, BRI2 is a specific inhibitor that reduces secretases' access to APP in the intracellular compartments where APP is normally processed.
Matsuda
Shuji
S
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Matsuda
Yukiko
Y
Snapp
Erik L
EL
D'Adamio
Luciano
L
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D011499:Protein Processing, Post-Translational; D022161:Transport Vesicles / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D053829:Amyloid Precursor Protein Secretases