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J. Biol. Chem., Vol. 277, Issue 48, 46518-46526, November 29, 2002
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From the Departments of The calcium-independent receptor of
Post-translational Proteolytic Processing of the
Calcium-independent Receptor of
-Latrotoxin (CIRL), a Natural
Chimera of the Cell Adhesion Protein and the G Protein-coupled
Receptor
ROLE OF THE G PROTEIN-COUPLED RECEPTOR PROTEOLYSIS SITE (GPS)
MOTIF*
,§,,§,, and¶
Pharmacology and
¶ Physiology and Neuroscience and the § Skirball
Institute, New York University School of Medicine, New York, New
York 10016
-latrotoxin (CIRL), a neuronal cell surface receptor implicated in
the regulation of exocytosis, is a natural chimera of the cell adhesion
protein and the G protein-coupled receptor (GPCR). In contrast with
canonic GPCRs, CIRL consists of two heterologous non-covalently bound subunits, p120 and p85, due to endogenous proteolytic processing of the
receptor precursor in the endoplasmic reticulum. Extracellularly oriented p120 contains hydrophilic cell adhesion domains, whereas p85
resembles a generic GPCR. We determined that the site of the CIRL
cleavage is located within a juxtamembrane Cys- and Trp-rich domain of
the N-terminal extracellular region of CIRL. Mutations in this domain
make CIRL resistant to the cleavage and impair its trafficking.
Therefore, we have named it GPS for G protein-coupled receptor proteolysis site. The GPS motif is
found in homologous adhesion GPCRs and thus defines a novel receptor
family. We postulate that the proteolytic processing and two-subunit
structure is a common characteristic feature in the family of
GPS-containing adhesion GPCRs.
*
This work was supported by NINDS National Institutes of
Health Grant R01NS35098 (to A. G. P.), NIGMS National Institutes of Health Grant R01GM59699 (to K. I.), and National Institutes of Health
Shared Instrumentation Grant 1 S10 RR14662-01 (to T. A. N.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmacology, New York University Medical Center, 550 1st Ave.,
MSB-320A, New York, NY 10016. Tel.: 212-263-5969; Fax: 212-263-7133;
E-mail: petrea01@med.nyu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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