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Energy landscapes of a mechanical prion and their implications for the molecular
mechanism of long-term memory
#MMPMID27091989
Chen M
; Zheng W
; Wolynes PG
Proc Natl Acad Sci U S A
2016[May]; 113
(18
): 5006-11
PMID27091989
show ga
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
?-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 ? to ? is shown to be
concentration dependent, with the transition barrier decreasing with increased
concentration. We observe that a mechanical pulling force can facilitate the
?-helix to ?-sheet (?-to-?) 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.
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