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

Abstract

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 Drosophila 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.

Tau amyloidogenesis begins with a loss of its conformational polymorphism

“…In order to understand whether this regulation is exerted at the monomer level and to further explore the molecular details of the early tau amyloid pathway, we have Figure S1). QBP1 was initially developed to inhibit the aggregation the expanded polyQ tracts and was found to prevent the toxic β -sheet conformational transition in the monomer (Nagai et al 2007), a plausible species that would act as a nucleus for aggregation (Hervas et al 2020) in a "nucleation growth" model (S. Chen, Ferrone, and Wetzel 2002;Hervas et al 2020). The lack of inhibitor action on tau could be due to incompatibilities with either the physico-chemical properties of the protein, such as not having polyQ segments, or with the molecular mechanism underlying its amyloidogenic process, or to both.…”

“…Tau has been extensively studied by structural (Jeganathan et al 2008;Mukrasch et al 2009;Fitzpatrick et al 2017;Falcon et al 2018;W. Zhang et al 2020), single-molecule (SM) (Wegmann et al 2011;Manger et al 2017) and computational approaches (Larini et al 2013).…”

Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation

“…Indeed, while both Q/H-rich stretches appear rather disordered in Orb2 amyloids formed in vitro (Cervantes et al 2016), Orb2 aggregation and memory consolidation can be blocked in Drosophila by a peptide which inhibits polyglutamine aggregation (Hervás et al, 2016). Very recently, the elucidation of the structure of physiological Orb2 amyloid isolated directly from Drosophila fly brains has shown that the main Q/H-rich stretch does in fact form the physiologically relevant amyloid structure (Hervás et al, 2020a). This amyloid features three-fold symmetry and side chain to mainchain H-bonds (Sup .…”

“…The participation of numerous His residues in the amyloid core provides a singular mechanism for amyloid destabilization through acidification. Intriguingly, the first nine residues of Orb2A, while relevant for triggering aggregation (Majumdar et al, 2012), do not contribute to the amyloid core, which is composed of the more abundant Orb2B isoform (Hervás et al, 2020a) (Sup. Fig.…”

Divergent CPEB prion-like domains reveal different assembly mechanisms for a generic amyloid-like fold

“…While Orb2 monomers repress synaptic translation, the amyloid state enhances it (Hervas et al 2020;Khan et al 2015). Similarly, the neuronal-specific ApCPEB isoform can exist in at least two different conformational states: a soluble form and a β sheet-rich amyloid form with enhanced binding capacity to target mRNAs (Si, Lindquist, and Kandel 2003;Raveendra et al 2013).…”