How a time-limited experience creates a long-lasting memory remains a fundamental, yet unanswered question. Experience-dependent aggregation of a prion-like protein, cytoplasmic polyadenylation element-binding (CPEB) protein, to a translationally active state has emerged as a plausible biochemical substrate of long-lasting memories.

However, the structural and functional features of aggregated CPEB in the brain remain unknown. Here, we report, the biochemical and structural characterization of endogenous aggregates of Orb2, the CPEB orthologue in Drosophila, extracted from 3 to 7-day-old adult fly brains. We find that Orb2 forms ~75 nm-long amyloid filaments with 3-fold symmetry.

The Orb2 filaments bind to target mRNAs and to its interacting partner CG4612 to enhance protein synthesis and can seed further translationally active aggregation. A cryo-EM structure of the filaments at 2.6 Å resolution reveals a protofilament core comprised of 31 amino acids residues of the prion-like domain (residues 176-206), which adopts a cross-β unit with a single hydrophilic hairpin stabilized by a tight interdigitated glutamine packing.

This study characterizes the first endogenous functional amyloid at the atomic level and provides insights into how self-sustaining amyloids could be a substrate of enduring yet malleable memories.

References:

¹ Hervás, R., Rau, M.J., Park, Y., Zhang, W., Murzin, A.G., Fitzpatrick, J.A.J., Scheres, S.H.W., and Si, K. (2020).  Cryo-EM structure of a neuronal functional amyloid implicated in memory persistence in Drosophila. Science (80). 367, 1230–1234
² Nil, Z., Hervás, R., Gerbich, T., Leal, P., Yu, Z., Saraf, A., Sardiu, M., Lange, J.J., Yi, K., Unruh, J., et al. (2019). Amyloid-like Assembly Activates a Phosphatase in the Developing Drosophila Embryo. Cell (2019) 178 (6)
³ Hervás, R., Li, L., Majumdar, A., Fernández-Ramírez, M. del C., Unruh, J.R., Slaughter, B.D., Galera-Prat, A., Santana, E., Suzuki, M., Nagai, Y., et al. Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation. PLOS Biol. (2016) 14