Cryo-EM structure of a neuronal functional amyloid implicated in memory persistence in Drosophila

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6483; pp. 1230 - 1234
• Main Authors: Hervas, Ruben, Rau, Michael J, Park, Younshim, Zhang, Wenjuan, Murzin, Alexey G, Fitzpatrick, James A J, Scheres, Sjors H W, Si, Kausik
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 13-03-2020
• Subjects: Amino acids; Amyloid - chemistry; Animals; Atomic structure; Chemical composition; Cryoelectron Microscopy; Drosophila; Drosophila melanogaster; Drosophila Proteins - chemistry; Electron microscopy; Filaments; Fruit flies; Glutamine; Glutamine - chemistry; Hydrophilicity; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Insects; Memory; Memory, Long-Term; mRNA Cleavage and Polyadenylation Factors - chemistry; Neurons - metabolism; Polyadenylation; Prion protein; Protein Aggregates; Protein Conformation; Proteins; Ribonucleic acid; RNA; RNA-binding protein; RNA-Binding Proteins - chemistry; Substrates; Transcription Factors - chemistry; Translation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aba3526

How long-lived memories withstand molecular turnover is a fundamental question. Aggregates of a prion-like RNA-binding protein, cytoplasmic polyadenylation element-binding (CPEB) protein, is a putative substrate of long-lasting memories. We isolated aggregated
CPEB, Orb2, from adult heads and determined its activity and atomic structure, at 2.6-angstrom resolution, using cryo-electron microscopy. Orb2 formed ~75-nanometer-long threefold-symmetric amyloid filaments. Filament formation transformed Orb2 from a translation repressor to an activator and "seed" for further translationally active aggregation. The 31-amino acid protofilament core adopted a cross-β unit with a single hydrophilic hairpin stabilized through interdigitated glutamine packing. Unlike the hydrophobic core of pathogenic amyloids, the hydrophilic core of Orb2 filaments suggests how some neuronal amyloids could be a stable yet regulatable substrate of memory.