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nRap GEP: A Novel Neural GDP/GTP Exchange Protein for Rap1 Small G Protein That Interacts with Synaptic Scaffolding Molecule (S-SCAM),☆☆

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Abstract

Synaptic scaffolding molecule (S-SCAM) has six PDZ domains through which it interacts with N-methyl-d-aspartate receptors and neuroligin at synaptic junctions. We isolated here a novel S-SCAM-binding protein. This protein has one PDZ, one Ras association, one Ras GDP/GTP exchange protein (Ras GEP) domain, and one C-terminal consensus motif for binding to PDZ domains. We named it nRap GEP (neural Rap GEP). nRap GEP moreover has an incomplete cyclic AMP (cAMP)-binding (CAB) domain. The domain organization of nRap GEP is similar to that of Epac/cAMP–guanine nucleotide exchange factor (GEF) I, except that Epac/cAMP–GEFI has complete CAB and Ras GEP domains but lacks the other two domains and the C-terminal motif. nRap GEP showed GEP activity for Rap1 but did not bind cAMP. nRap GEP was specifically expressed in rat brain. Immunohistochemical analysis revealed that nRap GEP and S-SCAM were localized at synaptic areas of the cerebellum. These results suggest that nRap GEP is a novel neural Rap1-specific GEP which is associated with S-SCAM.

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    Abbreviations used: PSD, postsynaptic density; SAP, synapse-associated protein; PDZ, PSD-95/Dlg-A/ZO-1; GK, guanylate kinase; NMDA, N-methyl-d-aspartate; SAPAP, SAP90/PSD-95-associated protein; GKAP, guanylate kinase-associated protein; DAP, hDLG-associated protein; S-SCAM, synaptic scaffolding molecule; GEP, GDP/GTP exchange protein; MAP, mitogen-activated protein; GAP, GTPase activating protein; TBST, Tris-buffed saline containing 0.05% Tween 20; pAb, polyclonal antibody; mAb, monoclonal antibody; RA, Ras association; CAB, cAMP-binding; GEF, guanine nucleotide exchange factor; GTPγS, guanosine 5′-(3-O-thio)triphosphate; GFP, green fluorescent protein; SPM, synaptic plasma membrane.

    ☆☆

    The work performed at Osaka University Graduate School of Medicine/Faculty of Medicine was supported by grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Science, Sports, and Culture, Japan (1998), and by grants from the Human Frontier Science Program (1998).

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    To whom correspondence should be addressed at Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Osaka, Japan. Fax: +81-6-6879-3419. E-mail: [email protected].

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