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Article: Phase separation modulates the functional amyloid assembly of human CPEB3
Title | Phase separation modulates the functional amyloid assembly of human CPEB3 |
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Authors | |
Issue Date | 1-Jul-2023 |
Publisher | Elsevier |
Citation | Progress in Neurobiology, 2023 How to Cite? |
Abstract | How functional amyloids are regulated to restrict their activity is poorly understood. The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that adopts an amyloid state key for memory persistence. Its monomer represses the translation of synaptic target mRNAs while phase separated, whereas its aggregated state acts as a translational activator. Here, we have explored the sequence-driven molecular determinants behind the functional aggregation of human CPEB3 (hCPEB3). We found that the intrinsically disordered region (IDR) of hCPEB3 encodes both an amyloidogenic and a phase separation domain, separated by a poly-A-rich region. The hCPEB3 amyloid core is composed by a hydrophobic region instead of the Q-rich stretch found in the Drosophila orthologue. The hCPEB3 phase separation domain relies on hydrophobic interactions with ionic strength dependence, and its droplet ageing process leads to a liquid-to-solid transition with the formation of a non-fibril-based hydrogel surrounded by starburst droplets. Furthermore, we demonstrate the differential behavior of the protein depending on its environment. Under physiological-like conditions, it can establish additional electrostatic interactions with dissolved ions, increases the stability of its liquid droplets and follows a condensation-based amyloid pathway. |
Persistent Identifier | http://hdl.handle.net/10722/338992 |
ISSN | 2023 Impact Factor: 6.7 2023 SCImago Journal Rankings: 2.605 |
DC Field | Value | Language |
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dc.contributor.author | de Mingo, Daniel Ramírez | - |
dc.contributor.author | López-García, Paula | - |
dc.contributor.author | Vaquero, María Eugenia | - |
dc.contributor.author | Hervás, Rubén | - |
dc.contributor.author | Laurents, Douglas V | - |
dc.contributor.author | Carrión-Vázquez, Mariano | - |
dc.date.accessioned | 2024-03-11T10:33:02Z | - |
dc.date.available | 2024-03-11T10:33:02Z | - |
dc.date.issued | 2023-07-01 | - |
dc.identifier.citation | Progress in Neurobiology, 2023 | - |
dc.identifier.issn | 0301-0082 | - |
dc.identifier.uri | http://hdl.handle.net/10722/338992 | - |
dc.description.abstract | <p>How functional amyloids are regulated to restrict their activity is poorly understood. The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that adopts an amyloid state key for memory persistence. Its monomer represses the translation of synaptic target mRNAs while phase separated, whereas its aggregated state acts as a translational activator. Here, we have explored the sequence-driven molecular determinants behind the functional aggregation of human CPEB3 (hCPEB3). We found that the intrinsically disordered region (IDR) of hCPEB3 encodes both an amyloidogenic and a phase separation domain, separated by a poly-A-rich region. The hCPEB3 amyloid core is composed by a hydrophobic region instead of the Q-rich stretch found in the Drosophila orthologue. The hCPEB3 phase separation domain relies on hydrophobic interactions with ionic strength dependence, and its droplet ageing process leads to a liquid-to-solid transition with the formation of a non-fibril-based hydrogel surrounded by starburst droplets. Furthermore, we demonstrate the differential behavior of the protein depending on its environment. Under physiological-like conditions, it can establish additional electrostatic interactions with dissolved ions, increases the stability of its liquid droplets and follows a condensation-based amyloid pathway.</p> | - |
dc.language | eng | - |
dc.publisher | Elsevier | - |
dc.relation.ispartof | Progress in Neurobiology | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | Phase separation modulates the functional amyloid assembly of human CPEB3 | - |
dc.type | Article | - |
dc.identifier.doi | 10.1016/j.pneurobio.2023.102540 | - |
dc.identifier.eissn | 1873-5118 | - |
dc.identifier.issnl | 0301-0082 | - |