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J. Biol. Chem., Vol. 283, Issue 1, 301-310, January 4, 2008

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Mind Bomb-2 Is an E3 Ligase That Ubiquitinates the N-Methyl-D-aspartate Receptor NR2B Subunit in a Phosphorylation-dependent Manner^*

From the Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608

The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity. Post-translational modifications of NMDARs, such as phosphorylation, alter both the activity and trafficking properties of NMDARs. Ubiquitination is increasingly being recognized as another post-translational modification that can alter synaptic protein composition and function. We identified Mind bomb-2 as an E3 ubiquitin ligase that interacts with and ubiquitinates the NR2B subunit of the NMDAR in mammalian cells. The protein-protein interaction and the ubiquitination of the NR2B subunit were found to be enhanced in a Fyn phosphorylation-dependent manner. Immunocytochemical studies reveal that Mind bomb-2 is localized to postsynaptic sites and colocalizes with the NMDAR in apical dendrites of hippocampal neurons. Furthermore, we show that NMDAR activity is down-regulated by Mind bomb-2. These results identify a specific E3 ubiquitin ligase as a novel interactant with the NR2B subunit and suggest a possible mechanism for the regulation of NMDAR function involving both phosphorylation and ubiquitination.

Received for publication, July 6, 2007 , and in revised form, October 10, 2007.

^* This work was supported in part by the NIAAA, National Institutes of Health Grant R01AA013438-01A1 (to D. R.), the Alcoholic Beverage Medical Research Foundation (to D. R.), Swiss National Science Foundation (to R. J.), and the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (to D. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Present address: Dept. of Neuroscience, University of Pennsylvania, Philadelphia, PA.

² Present address: MRC Clinical Sciences Centre, Imperial College of Science Technology and Medicine, London, UK.

³ To whom correspondence should be addressed: Gallo Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3150; Fax: 510-985-3101; E-mail: dorit.ron{at}ucsf.edu.

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