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

Gallo Research Center, Department of Neurology, University of California-San Francisco, Emeryville, CA 94608, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2008; 283(1):301-10. DOI: 10.1074/jbc.M705580200
Source: PubMed

ABSTRACT 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.

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Available from: Claire Thornton, Sep 01, 2015
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    • "Several different regulatory mechanisms have been identified thus far. It was recently reported that the NR2B subunit of the NMDA receptor can be ubiquitinated by the E3 ligase Mind bomb-2 (Mib2) [57]. Although it is unclear if the ubiquitination of NR2B leads to receptor endocytosis, degradation, or other downstream signaling cascades, the same study demonstrated the possibility that ubiquitination can regulate the function of the NMDA receptor. "
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    ABSTRACT: The ubiquitin proteasome system (UPS) is one of the principle mechanisms for the regulation of protein homeostasis in mammalian cells. In dynamic cellular structures such as neuronal synapses, UPS and protein translation provide an efficient way for cells to respond promptly to local stimulation and regulate neuroplasticity. The majority of research related to long-term plasticity has been focused on the postsynapses and has shown that ubiquitination and subsequent degradation of specific proteins are involved in various activity-dependent plasticity events. This review summarizes recent achievements in understanding ubiquitination of postsynaptic proteins and its impact on synapse plasticity and discusses the direction for advancing future research in the field.
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    • "It has been suggested that the Amyloid-Beta-induced loss of synapses requires the activation of extra-synaptic NMDA receptors containing the GluN2B subunit (Shankar et al., 2007; Talantova et al., 2013), underscoring the importance of regulating NMDA receptor levels and localization in AD pathology. GluN2B is ubiquitinated in response to synaptic activity by the E3 ligase Mind Bomb-2 (Jurd et al., 2008). Fbxo2, described above for its regulation of APP, also regulates the levels of NMDA receptors in vitro by facilitating the activity-dependent ubiquitination and elimination of the NMDA receptor subunit GluN1 (Kato et al., 2005). "
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    • "NMDAR GluN2B subunits on the other hand are ubiquitinated by the RING family E3 ligase Mindbomb2 (Mib2), which is localized to the PSD and directly interacts with and ubiquitinates GluN2B to downregulate NMDAR activity [46]. Phosphorylation by the Src-family protein-tyrosine kinase Fyn enhances the protein-protein interaction between Mib2 and GluN2B, and subsequently, the ubiquitination of GluN2B by Mib2 [46]. "
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    ABSTRACT: The human brain is made up of an extensive network of neurons that communicate by forming specialized connections called synapses. The amount, location, and dynamic turnover of synaptic proteins, including neurotransmitter receptors and synaptic scaffolding molecules, are under complex regulation and play a crucial role in synaptic connectivity and plasticity, as well as in higher brain functions. An increasing number of studies have established ubiquitination and proteasome-mediated degradation as universal mechanisms in the control of synaptic protein homeostasis. In this paper, we focus on the role of the ubiquitin-proteasome system (UPS) in the turnover of major neurotransmitter receptors, including glutamatergic and nonglutamatergic receptors, as well as postsynaptic receptor-interacting proteins.
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