Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o)
The most characteristic change in progressive dementia of Alzheimer's type is a tissue deposit of amyloid beta/A4 protein, which is derived from its precursor protein APP (ref.2). Structural alterations of APP are implicated in the pathogenesis of Alzheimer's disease, but it is not known how they cause the disease. Although APP has a receptor-like architecture, is located on the neuronal surface, and has a conserved cytoplasmic domain, no receptor function has been demonstrated for APP. Here we report that APP forms a complex with G(o), a major GTP-binding protein in brain. The cytoplasmic APP sequence His 657-Lys 676 shows a specific G(o)-activating function and is necessary for complex formation. G(o) protein treated with GTP-gamma S lost the ability to associate with APP. This suggests that APP is a receptor coupled to G(o) and that abnormal APP-G(o) signalling is involved in the Alzheimer's disease process.
Nishimoto
I
I
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Okamoto
T
T
Matsuura
Y
Y
Takahashi
S
S
Okamoto
T
T
Murayama
Y
Y
Ogata
E
E
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007313:Insecta; D007700:Kinetics; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D015183:Restriction Mapping; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins