Title: Protein Degradation in Learning and Memory

Abstract: Long-term potentiation (LTP) requires the persistent activity of CaMKII at the synapse, yet how this signal is eventually terminated remains poorly understood. In this presentation, we will discuss how UBE3A — the E3 ubiquitin ligase lost in Angelman Syndrome — acts as a selective regulator of activated CaMKII. Using a combination of CRISPR screening, reconstituted biochemistry, and cryo-EM, we show that UBE3A recognizes the substrate binding pocket of CaMKII, revealing a competition between substrates and the degradation machinery. These findings suggest a model in which targeted degradation of CaMKII resets the capacity for new synaptic plasticity.