Ligand-dependent G Protein Coupling Function of Amyloid Transmembrane Precursor (*)
- Takashi Okamoto(1)(§),
- Shizu Takeda(1),
- Yoshitake Murayama(2),
- Etsuro Ogata(3) and
- Ikuo Nishimoto(1)(§)
- From the (1)Cardiovascular Research Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, the
- (2)Fourth Department of Internal Medicine, Tokyo University School of Medicine, 3-28-6 Mejirodai, Bunkyo-ku, Tokyo 112, Japan, and the
- (3)Cancer Research Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170, Japan
- § To whom correspondence should be addressed: Cardiovascular Research Center, Massachusetts General Hospital and Dept. of Medicine, Harvard Medical School, 149 13th St., Charlestown, MA 02129. Tel.: 617-726-4348; Fax: 617-726-5806; nishimoto{at}helix.mgh.harvard.edu
Abstract
Amyloid precursor protein (APP), a transmembrane precursor of β-amyloid, possesses a function whereby it associates with Go through its cytoplasmic His
-Lys
. Here we demonstrate that APP has a receptor function. In phospholipid vesicles consisting of baculovirally made APP
and brain trimeric Go, 22C11, a monoclonal antibody against the extracellular domain of APP, increased GTP
S binding and the turnover number of GTPase of Go without affecting its intrinsic GTPase activity. This effect of 22C11 was specific among various antibodies and was observed
neither in Go vesicles nor in APP
/G
vesicles. In APP
/Go vesicles, synthetic APP
, the epitope of 22C11, competitively antagonized the action of 22C11. Monoclonal antibody against APP
, the Go binding domain of APP
, specifically blocked 22C11-dependent activation of Go. Therefore, APP has a potential receptor function whereby it specifically activates Go in a ligand-dependent and ligand-specific manner.
Footnotes
-
↵* This work was supported in part by Bristol-Myers Squibb and by grants from the Ministry of Education, Science, and Culture of Japan, Chugai, and Hoechst. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- AD
-
Alzheimer's disease
- APP
-
amyloid precursor protein
- G protein
-
guanine nucleotide-binding protein with trimeric composition
- FAD
-
familial Alzheimer's disease
- mAb
-
monoclonal antibody
- GTP
S -
guanosine-5′-O-(3-thiotriphosphate)
- CHAPS
-
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.
-
- Received November 11, 1994.
- Revision received January 4, 1995.
