Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Abstract

Aplysia cytoplasmic polyadenylation element binding (CPEB) protein, a translational regulator that recruits mRNAs and facilitates translation, has been shown to be a key component in the formation of long-term memory. Experimental data show that CPEB exists in at least a low-molecular weight coiled-coil oligomeric form and an amyloid fiber form involving the Q-rich domain (CPEB-Q). Using a coarse-grained energy landscape model, we predict the structures of the low-molecular weight oligomeric form and the dynamics of their transitions to the β-form. Up to the decamer, the oligomeric structures are predicted to be coiled coils. Free energy profiles confirm that the coiled coil is the most stable form for dimers and trimers. The structural transition from α to β is shown to be concentration dependent, with the transition barrier decreasing with increased concentration. We observe that a mechanical pulling force can facilitate the α-helix to β-sheet (α-to-β) transition by lowering the free energy barrier between the two forms. Interactome analysis of the CPEB protein suggests that its interactions with the cytoskeleton could provide the necessary mechanical force. We propose that, by exerting mechanical forces on CPEB oligomers, an active cytoskeleton can facilitate fiber formation. This mechanical catalysis makes possible a positive feedback loop that would help localize the formation of CPEB fibers to active synapse areas and mark those synapses for forming a long-term memory after the prion form is established. The functional role of the CPEB helical oligomers in this mechanism carries with it implications for targeting such species in neurodegenerative diseases.long-term memory | mechanical prion | protein aggregation | Q-rich protein I t is widely believed that learning involves the modification in number, strength, and structure of specific localized synaptic connections. Although short-term memory formation occurs without protein synthesis, establishing long-term memory (LTM) involves protein synthesis localized at the synapse area, thus requiring a stable translational regulatory system that activates mRNA and protein synthesis in the synapse (1-3). It has long been recognized that the relatively short half-life of most proteins in eukaryotic cells (4) poses questions about the long timescales over which memories can be retained. It has been suggested that forming a very stable prion could provide a mechanism for achieving memory longevity (5, 6). An excellent candidate species has emerged from the works of Kandel and coworkers (1-3) and Lindquist and coworker (6) on cytoplasmic polyadenylation element binding (CPEB). It has been established, in Aplysia, that Aplysia cytoplasmic polyadenylation element binding (ApCPEB) activates mRNA and mediates synaptic protein synthesis for at least 72 h and that it does so by taking on a functional prion-like form (3, 7). Forming the prion is, thus, a key element in LTM formation and maintenance.Prions were first proposed as protein-only infectious particles causing Creu...

Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington’s disease

“…Mechanical forcedriven aggregation was seen in our simulations of another Q-rich protein implicated in the formation of long-term memory, CPEB (27). Mechanical coupling of HTT with the cytoskeleton should be considered a candidate for the initial stage of forming inclusion bodies.…”

“…S10C). By itself, the NT17 segment also has a very strong propensity to aggregate as a coiled coil; α-helical aggregation followed by a structural transition to the β-strand form occurs in another Q-rich protein, CPEB, which has been implicated in long-term memory (27). Coiled coils seem to play an essential role in aggregation of these proteins found in neurons (40).…”

“…To overcome these problems, we use coarse-grained simulations of the aggregation of HTT exon 1-encoded fragments that use the AWSEM force field. While being efficient to simulate, the AWSEM force field can predict the structures of protein monomers (22-24) and predict details of assembly into oligomers (9,(25)(26)(27)(28). We have already used the model to explore the detailed mechanisms of aggregation of pure polyQ peptides (9) and the peptide implicated in Alzheimer's disease (28), Aβ40.…”

The Aggregation Free Energy Landscapes of Polyglutamine Repeats

“…The AWSEM force field, while being efficient to simulate, also has been shown to predict the structures of protein monomers 13,14 as well as details of their assembly. 15–17 We have previously used the force field to study the free energy landscape of a mechanical prion, also rich in glutamine, that is involved in memory. 17 We find that while the simple polyQ peptides longer than 30 residues prefer a hairpin structure in the monomer, for shorter lengths an extended structure is favored.…”

The AWSEM-Amylometer: predicting amyloid propensity and fibril topology using an optimized folding landscape model

“…20 AWSEM has been fruitfully applied in recent years to many different problems of protein structure prediction, [20][21][22] protein association, 23 allosteric mechanism 24 and protein aggregation. [25][26][27][28][29] The AWSEM-Amylometer is based on the same energy model that is used in AWSEM molecular dynamics simulations but is able to detect amyloidogenic segments using a simple and efficient threading scheme over multiple fiber template structures. This scheme not only allows for the detection of amyloidogenic segments but also the prediction of the relative orientation of the amyloid β-strands in the fibril core.…”