A Novel Multiple PDZ Domain-containing Molecule Interacting withN-Methyl-d-aspartateReceptors and Neuronal Cell Adhesion Proteins

doi:10.1074/jbc.273.33.21105

A Novel Multiple PDZ Domain-containing Molecule Interacting withN-Methyl-d-aspartateReceptors and Neuronal Cell Adhesion Proteins*

From the ^‡Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan, the ^§Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050, and the ^¶Department of Molecular Biology and Biochemistry, Osaka University Medical School, Suita 565-0871, Japan

Abstract

At synaptic junctions, pre- and postsynaptic membranes are connected by cell adhesion and have distinct structures for specialized functions. The presynaptic membranes have a machinery for fast neurotransmitter release, and the postsynaptic membranes have clusters of neurotransmitter receptors. The molecular mechanism of the assembly of synaptic junctions is not yet clear. Pioneering studies identified postsynaptic density (PSD)-95/SAP90 as a prototypic synaptic scaffolding protein to maintain the structure of synaptic junctions. PSD-95/SAP90 belongs to a family of membrane-associated guanylate kinases and binds N-methyl-d-aspartate receptors, potassium channels, and neuroligins through the PDZ domains and GKAP/SAPAP/DAP through the guanylate kinase (GK) domain. We performed here a yeast two-hybrid screening for SAPAP-interacting molecules and identified a novel protein that has an inverse structure of membrane-associated guanylate kinases with an NH₂-terminal GK-like domain followed by two WW and five PDZ domains. It binds SAPAP through the GK-like domain and NMDA receptors and neuroligins through the PDZ domains. We named this protein S-SCAM (synaptic scaffolding molecule) because S-SCAM may assemble receptors and cell adhesion proteins at synaptic junctions.

Footnotes

↵* 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AF034863.
↵‖ To whom correspondence should be addressed: Dept. of Molecular Biology and Biochemistry, Osaka University Medical School, 2-2 Yamada-oka, Suita 565-0871, Japan. Tel.: 81-06-879-3410; Fax: 81-06-879-3419; E-mail: ytakai{at}molbio.med.osak-u.ac.jp.
Abbreviations:

PSD

postsynaptic density

NMDA

N-methyl-d-aspartate

NMDAR

NMDA receptor

GK

guanylate kinase

GKAP

guanylate kinase-associated protein

SAPAP

SAP90/PSD-95-associated protein

DAP

hDLG- and PSD-95-associated protein

S-SCAM

synaptic scaffolding molecule

DRPLA

dentatorubral pallidoluysian atrophy

GST

glutathioneS-transferase

SPM fraction

synaptosomal membrane fraction.
- Received April 1, 1998.
- Revision received May 5, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.