LIGAND-DEPENDENT G-PROTEIN COUPLING FUNCTION OF AMYLOID TRANSMEMBRANEPRECURSOR

Amyloid precursor protein (APP), a transmembrane precursor of beta-amy loid, possesses a function whereby it associates with G(o) through its cytoplasmic His(657)- Lys(676). Here we demonstrate that APP has a re ceptor function. In phospholipid vesicles consisting of baculovirally made APP(695) and brain trimeric G(o), 22C11, a monoclonal antibody ag ainst the extracellular domain of APP, increased GTP gamma S binding a nd the turnover number of GTPase of G(o) without affecting its intrins ic GTPase activity. This effect of 22C11 was specific among various an tibodies and was observed neither in G(o) vesicles nor in APP(695)/G(i 2) vesicles. In APP(695)/G(o) vesicles, synthetic APP(66-81), the epit ope of 22C11, competitively antagonized the action of 22C11. Monoclona l antibody against APP(657-676), the G(o) binding domain of APP(695), specifically blocked 22C11-dependent activation of G(o). Therefore, AP P has a potential receptor function whereby it specifically activates G(o) in a ligand-dependent and ligand-specific manner.