Ligand-dependent G Protein Coupling Function of Amyloid Transmembrane Precursor

Abstract

Amyloid precursor protein (APP), a transmembrane precursor of beta-amyloid, possesses a function whereby it associates with G(o) through its cytoplasmic His657-Lys676. Here we demonstrate that APP has a receptor function. In phospholipid vesicles consisting of baculovirally made APP695 and brain trimeric G(o), 22C11, a monoclonal antibody against the extracellular domain of APP, increased GTP gamma S binding and the turnover number of GTPase of G(o) without affecting its intrinsic GTPase activity. This effect of 22C11 was specific among various antibodies and was observed neither in G(o) vesicles nor in APP695/Gi2 vesicles. In APP695/G(o) vesicles, synthetic APP66-81, the epitope of 22C11, competitively antagonized the action of 22C11. Monoclonal antibody against APP657-676, the G(o) binding domain of APP695, specifically blocked 22C11-dependent activation of G(o). Therefore, APP has a potential receptor function whereby it specifically activates G(o) in a ligand-dependent and ligand-specific manner.

A primordial dopamine D1‐like adenylyl cyclase‐linked receptor from Drosophila melanogaster displaying poor affinity for benzazepines

“…Interestingly enough, this sequence motif may be inverted in dDA1 (BXXABB). Other putative G protein-activating motifs, BBXB, [41] are, however, present in both the amino (KHVK) and middle (RRPK; KKFK) portions of this loop. In addition to the third cytoplasmic loop, sequences within the carboxyl-tail have been shown to determine G protein specificity [42].…”

Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

“…These include the interaction with the heterotrimeric G protein Go (2), a 59-kDa ubiquitously expressed protein named APP-BP1 (3), the X11 protein (4), the neuron-abundant Fe65 protein, and an Fe65-like protein (4 -6). It was shown that intact APP binds to oligomeric Go protein and that the intracellular region of APP spanning residues 657-676 activates Go (2,7). Furthermore, the interaction of APP with a monoclonal antibody directed against its extracellular domain mimics a ligand-receptor binding that triggers Go activation (7).…”

“…It was shown that intact APP binds to oligomeric Go protein and that the intracellular region of APP spanning residues 657-676 activates Go (2,7). Furthermore, the interaction of APP with a monoclonal antibody directed against its extracellular domain mimics a ligand-receptor binding that triggers Go activation (7). APP-BP1 interacts both in vitro and in vivo with the carboxyl-terminal region of APP, which represents its intracellular domain.…”

Characterization of the Major Bovine Brain Go α Isoforms

“…Indeed, there is evidence that amyloid precursor protein, critical in the formation of amyloid plaques associated with Alzheimer's disease, functions as a receptor for G o (66,67). Since several functions for G o have been proposed, structural heterogeneity resulting from both alternative splicing and variable modification may allow G o to perform divergent functions.…”