Demixing is a default process for biological condensates formed via phase separation

• 成果类型: Article
• 署名作者: Zhu, Shihan; Shen, Zeyu; Wu, Xiandeng; Han, Wenyan; Jia, Bowen; Lu, Wei; Zhang, Mingjie
• 署名单位: Hong Kong University of Science & Technology; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); Southern University of Science & Technology
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12226
• DOI: 10.1126/science.adj7066
• 发表日期: 2024-05-24
• 页码: 920-928
• 关键词: inhibitory synapses; excitatory synapses; glycine receptors; dendritic spines; collybistin; gephyrin; differentiation; transmission; complexes; diffusion

摘要

Excitatory and inhibitory synapses do not overlap even when formed on one submicron-sized dendritic protrusion. How excitatory and inhibitory postsynaptic cytomatrices or densities (e/iPSDs) are segregated is not understood. Broadly, why membraneless organelles are naturally segregated in cellular subcompartments is unclear. Using biochemical reconstitutions in vitro and in cells, we demonstrate that ePSDs and iPSDs spontaneously segregate into distinct condensed molecular assemblies through phase separation. Tagging iPSD scaffold gephyrin with a PSD-95 intrabody (dissociation constant similar to 4 nM) leads to mistargeting of gephyrin to ePSD condensates. Unexpectedly, formation of iPSD condensates forces the intrabody-tagged gephyrin out of ePSD condensates. Thus, instead of diffusion-governed spontaneous mixing, demixing is a default process for biomolecules in condensates. Phase separation can generate biomolecular compartmentalization specificities that cannot occur in dilute solutions.