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Papers In Press, published online ahead of print May 12, 2004
J. Biol. Chem, 10.1074/jbc.M402316200
Submitted on March 1, 2004
Revised on May 10, 2004
Accepted on May 12, 2004

Spatial and temporal regulation of RACK1 function and NMDA receptor activity through WD40 motif-mediated dimerization

Claire Thornton, Ka-Choi Tang, Khanhky Phamluong, Ken Luong, Alicia Vagts, Donna Nikanjam, Rami Yaka, and Dorit Ron

Department of Neurology, University of California San Francisco,, Emeryville, CA 94608

Corresponding Author: dorit{at}itsa.ucsf.edu

Efficient signaling requires accurate spatial and temporal compartmentalization of proteins. RACK1 is a scaffolding protein that fulfils this role through interaction of binding partners with one of its seven WD40 domains. Recently, we identified the kinase Fyn and the NR2B subunit of the N-Methyl D-Aspartate receptor (NMDAR) as binding partners of RACK1. Scaffolding of Fyn in close proximity to its substrate, NR2B, by RACK1, inhibits Fyn phosphorylation of NR2B and thereby negatively regulates channel function. We found that Fyn and NR2B share the same binding site on RACK1, however their binding to RACK1 is not mutually exclusive (1). We therefore tested the hypothesis that RACK1 forms a homodimer that allows the simultaneous binding of Fyn and NR2B. We found that RACK1 binds to itself both in vitro and in the brain. Deletion analyses identified a RACK1-RACK1 dimer-binding site within the 4th WD40 repeat, and application of the 4th WD40 repeat or a peptide derivative to hippocampal slices inhibited NMDAR activity. We further found that in hippocampal slices, both RACK1 and NR2B associated with another WD40 protein, the beta subunit of G protein (Gb), previously shown to heterodimerize with RACK1 in vitro (2). However, activation of the pituitary adenylate cyclase polypeptide (1-38) (PACAP(1-38)) G protein-coupled receptor (GPCR), previously found to induce the dissociation of RACK1 from the NMDAR complex (3), attenuated the association of Gb with RACK1 and NR2B. Based on these results, we propose that WD40-mediated homo and heterodimerization of RACK1 mediate the formation of a transient signaling complex that includes the NMDAR, a G protein and Fyn.


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