Thermodynamic modulation of gephyrin condensation by inhibitory synapse components
Phase separation drives compartmentalization of intracellular contents into various biomolecular condensates. Individual condensate components are thought to differentially contribute to the organization and function of condensates. However, how intermolecular interactions among constituent biomolecules modulate the phase behaviors of multicomponent condensates remains unclear. Here, we used core components of the inhibitory postsynaptic density (iPSD) as a model system to quantitatively probe how the network of intra- and intermolecular interactions defines the composition and cellular distribution of biomolecular condensates. We found that oligomerization-driven phase separation of gephyrin, an iPSD-specific scaffold, is critically modulated by an intrinsically disordered linker region exhibiting minimal homotypic attractions. Other iPSD components, such as neurotransmitter receptors, differentially promote gephyrin condensation through distinct binding modes and affinities. We further demonstrated that the local accumulation of scaffold-binding proteins at the cell membrane promotes the nucleation of gephyrin condensates in neurons. These results suggest that in multicomponent systems, the extent of scaffold condensation can be fine-tuned by scaffold-binding factors, a potential regulatory mechanism for self-organized compartmentalization in cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 12 vom: 19. März, Seite e2313236121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Gyehyun [VerfasserIn] |
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| Links: |
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| Themen: |
Biomolecular condensate |
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| Anmerkungen: |
Date Completed 13.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2313236121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Phase separation drives compartmentalization of intracellular contents into various biomolecular condensates. Individual condensate components are thought to differentially contribute to the organization and function of condensates. However, how intermolecular interactions among constituent biomolecules modulate the phase behaviors of multicomponent condensates remains unclear. Here, we used core components of the inhibitory postsynaptic density (iPSD) as a model system to quantitatively probe how the network of intra- and intermolecular interactions defines the composition and cellular distribution of biomolecular condensates. We found that oligomerization-driven phase separation of gephyrin, an iPSD-specific scaffold, is critically modulated by an intrinsically disordered linker region exhibiting minimal homotypic attractions. Other iPSD components, such as neurotransmitter receptors, differentially promote gephyrin condensation through distinct binding modes and affinities. We further demonstrated that the local accumulation of scaffold-binding proteins at the cell membrane promotes the nucleation of gephyrin condensates in neurons. These results suggest that in multicomponent systems, the extent of scaffold condensation can be fine-tuned by scaffold-binding factors, a potential regulatory mechanism for self-organized compartmentalization in cells | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a phase separation | |
| 650 | 4 | |a polyphasic linkage | |
| 650 | 4 | |a synapse | |
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| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Carrier Proteins |2 NLM | |
| 700 | 1 | |a Kim, Seungjoon |e verfasserin |4 aut | |
| 700 | 1 | |a Hwang, Da-Eun |e verfasserin |4 aut | |
| 700 | 1 | |a Eom, Yu-Gon |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Gyubin |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Hye Yoon |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Jeong-Mo |e verfasserin |4 aut | |
| 700 | 1 | |a Ko, Jaewon |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Yongdae |e verfasserin |4 aut | |
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