Mind bomb-2 is an E3 ligase that ubiquitinates the N-methyl-D-aspartate receptor NR2B subunit in a phosphorylation-dependent manner.
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.
Jurd
Rachel
R
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Thornton
Claire
C
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Wang
Jun
J
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Luong
Ken
K
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Phamluong
Khanhky
K
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Kharazia
Viktor
V
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Gibb
Stuart L
SL
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
Ron
Dorit
D
Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608. Electronic address: dorit.ron@ucsf.edu.
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D025801:Ubiquitin; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; D051076:Proto-Oncogene Proteins c-fyn