A structural dynamics model for how CPEB3 binding to SUMO2 can regulate translational control in dendritic spines

Abstract

A prion-like RNA-binding protein, CPEB3, can regulate local translation in dendritic spines. CPEB3 monomers repress translation, whereas CPEB3 aggregates activate translation of its target mRNAs. However, the CPEB3 aggregates, as long-lasting prions, may raise the problem of unregulated translational activation. Here, we propose a computational model of the complex structure between CPEB3 RNA-binding domain (CPEB3-RBD) and small ubiquitin-like modifier protein 2 (SUMO2). Free energy calculations suggest that the allosteric effect of CPEB3-RBD/SUMO2 interaction can amplify the RNA-binding affinity of CPEB3. Combining with previous experimental observations on the SUMOylation mode of CPEB3, this model suggests an equilibrium shift of mRNA from binding to deSUMOylated CPEB3 aggregates to binding to SUMOylated CPEB3 monomers in basal synapses. This work shows how a burst of local translation in synapses can be silenced following a stimulation pulse, and explores the CPEB3/SUMO2 interplay underlying the structural change of synapses and the formation of long-term memories.

Author summary

Local translation of specific synaptic proteins provides the molecular basis for the structural change in dendritic spines, which is essential for long-term memories. A functional prion-like RNA-binding protein, CPEB3, has been proposed as a synaptic tag to regulate local translation in dendritic spines. More interestingly, the soluble CPEB3 monomers repress translation, whereas the CPEB3 aggregates activate the translation of its target mRNAs. The CPEB3 aggregates, however, that act as long-lasting prions providing “conformational memory”, may raise the problem of translational activation being unregulated. Here, we propose a computational model of the complex structure between CPEB3 RNA-binding domain (CPEB3-RBD) and small ubiquitin-like modifier protein 2 (SUMO2). Free energy calculations suggest that the allosteric binding of CPEB3 with SUMO2 can confine the CPEB3-RBD to a conformation that favors RNA-binding, and thereby can amplify its RNA-binding affinity. Combining this model with previous experiments showing that CPEB3 monomers are SUMOylated in basal synapses but become deSUMOylated and start to aggregate upon stimulation, we suggest a way in which the translational control of CPEB3 can be switched back to a repressive mode after a stimulation pulse, through an RNA binding shift from binding to CPEB3 fibers to binding to SUMOylated CPEB3 monomers in basal synapses.