UCLA

The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a functional prion thought to modulate protein synthesis at synapses and enable consolidation of long-term memory in neurons. The biophysical characteristics of the prion state may facilitate the endurance of CPEB3 in environments with high molecular turnover and enable rapid aggregation and localization of targets to subcellular sites. Truncations to the CPEB3 prion-like domain cause loss of stimulation induced protein upregulation and impede long-term potentiation in mice, highlighting the critical role of its putative prion conformation.

The prion state often requires polypeptides to adopt beta-sheet rich conformations of amyloid to generate and propagate faithful conformations in fluctuating environments, an alluring feature if controlled properly. Because of their association with neurodegenerative diseases, functional amyloid proteins and their regulation in the refined structure of the brain are not entirely understood. CPEB3 undergoes extensive post-translational modifications that control its subcellular localization and activity. Proper shuttling of the prion-like protein from RNA storage granules to polysomes is thought to be a critical component in its ability to exist within the homeostasis of neurons.

The work presented in this dissertation aims to determine the ability of CPEB3’s prion-like domain to form amyloid conformations and the role of this conformation in translation regulation. Through in vitro experiments investigating the ordered amyloid core of CPEB3, reversibility and lack of stability are observed as key differences in CPEB3 fibrils when compared to pathogenic counterparts. The data provide insights into the reversible amyloid core and show its requirement for proper storage and translation regulation in neurons. These results bridge the studies from in vitro generated structure to supramolecular assemblies observed inside of neurons. The native environments and structured complexes begin to show potential conformations of CPEB3 that are complementary to its function.