Dendritic spines are tiny membranous protrusions on the dendrites of neurons. Dendritic spines change shape in response to input signals, thereby strengthening the connections between neurons. The growth and stabilization of dendritic spines is thought to be essential for maintaining long-term memory. Actin cytoskeleton remodeling in spines is a key element of their formation and growth. More speculatively, the aggregation of CPEB3, a functional prion that binds RNA, has been reported to be involved in the maintenance of long-term memory. Here we study the interaction between actin and CPEB3 and propose a molecular model for the complex structure of CPEB3 and an actin filament (F-actin). The results of our computational modeling, including both energetic and structural analyses, are compared with novel data from peptide array experiments. Our model of the CPEB3/F-actin interaction suggests that F-actin potentially triggers the aggregation-prone structural transition of a short CPEB3 sequence by zipping it into a beta-hairpin form. We also propose that the CPEB3/F-actin interaction might be regulated by the SUMOylation of CPEB3, based on bioinformatic searches for potential SUMOylation sites as well as SUMO interacting motifs in CPEB3. On the basis of these results and the existing literature, we put forward a possible molecular mechanism underlying long-term memory that involves CPEB3’s binding to actin, its aggregation, and its regulation by SUMOylation.
- NSF-PAR ID:
- 10151199
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 116
- Issue:
- 38
- ISSN:
- 0027-8424
- Page Range / eLocation ID:
- 18937 to 18942
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca 2+ ), or vice versa, may provide insight into how Ca 2+ -CaM selects its target binding proteins. However, modeling of Ca 2+ -CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca 2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca 2+ . This feature that underlies the reciprocal relation between Ca 2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca 2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca 2+ binding in future studies.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.1911452116
