Presynaptic bouton compartmentalization and postsynaptic density-mediated glutamate receptor clustering via phase separation

Feng, Zhe; Wu, Xiandeng; Zhang, Mingjie

doi:10.1016/j.neuropharm.2021.108622

Cited by 11 publications

(7 citation statements)

References 133 publications

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“…These are fluid droplets that form by liquid-liquid phase separation (LLPS) of a wide range of intrinsically-disordered proteins (IDPs) [13]. They have numerous functions in the cell, including regulation of biochemical reactions [14], sequestering stalled RNA translation in stress granules [15], chromatin organization in the nucleus [16], and organizing the presynaptic axon and postsynaptic density in neurons [17,18]. Unlike lipid membranes, the formation of biomolecular condensates (BCs) in vivo is usually reversible: The cell actively assembles them to perform a function and they subsequently melt away [19].…”

Section: Introductionmentioning

confidence: 99%

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

et al. 2021

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Phospholipid membranes surround the cell and its internal organelles, and their multicomponent nature allows the formation of domains that are important in cellular signalling, the immune system, and bacterial infection. Cytoplasmic compartments are also created by the phase separation of intrinsically disordered proteins into biomolecular condensates. The ubiquity of lipid membranes and protein condensates raises the question of how three-dimensional droplets might interact with two-dimensional domains, and whether this coupling has physiological or pathological importance. Here, we explore the equilibrium morphologies of a dilute phase of a model disordered protein interacting with an ideal-mixing, two-component lipid membrane using coarse-grained molecular simulations. We find that the proteins can wet the membrane with and without domain formation, and form phase separated droplets bound to membrane domains. Results from much larger simulations performed on a novel non-von-Neumann compute architecture called POETS, which greatly accelerates their execution compared to conventional hardware, confirm the observations. Reducing the wall clock time for such simulations requires new architectures and computational techniques. We demonstrate here an inter-disciplinary approach that uses real-world biophysical questions to drive the development of new computing hardware and simulation algorithms.

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Section: Introductionmentioning

confidence: 99%

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

et al. 2021

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“…However, the current simulation results suggest that AMPAR(TARP) 4 and PSD-95 alone form transient small clusters, but are not sufficient to form a stable phase immediately under the membrane. These are not contradictory as PSD is known to be organized in a hierarchical manner with other scaffolding proteins, such as SAPAP, Shank, and Homer, which are also prone to form protein condensates in in vitro 3D systems (8, 58, 59), other than PSD-95, which is generally located in the upper hierarchy of PSD. At the bottom of the PSD hierarchy, the actin cytoskeleton further contributes to retaining the protein network and anchors the condensate to the cell body.…”

Section: Discussionmentioning

confidence: 99%

Postsynaptic protein assembly in three- and two-dimensions studied by mesoscopic simulations

Yamada

Takada

2023

Preprint

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Postsynaptic density (PSD) is a protein condensate located under the postsynaptic membrane that influences the localization of glutamate receptors and thus contributes to synaptic plasticity. Recent in vitro studies have revealed the formation of droplets of various soluble PSD proteins via liquid-liquid phase separation. However, it is unclear how these protein condensates are formed beneath the membrane and how they specifically affect the localization of glutamate receptors in the membrane. In this study, focusing on the mixture of a glutamate receptor complex, AMPAR-TARP, and a ubiquitous scaffolding protein, PSD-95, we constructed a mesoscopic model of protein-domain interactions in PSD and performed comparative molecular simulations. The results showed a sharp contrast in the phase behaviors of protein assemblies in three-dimension (3D) and those under the membrane (denoted as 2D). A mixture of a soluble variant of the AMPAR-TARP complex and PSD-95 in the 3D system resulted in a phase-separated condensate, which was consistent with the experimental results. However, with identical domain interactions, AMPAR-TARP embedded in the membrane formed clusters with PSD-95, but did not form a stable separated phase. The results indicate that the phase separation behaviors in the 3D and 2D systems were distinct. Stable phase separation is more difficult to achieve in and beneath the membrane than in 3D systems.

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“…Therefore, the PSD has also been recognized as a structural and functional hub [7], responsible for postsynaptic signaling and synaptic plasticity. The molecules of the PSD are believed to be grouped in nanoclusters around a few proteins and organized dynamically by phase separation [8]. Dendritic spines are highly dynamic elements and have the capacity to undergo structural changes that are tightly coordinated with synaptic function and modifications in glutamate receptors [9].…”

Section: Introductionmentioning

confidence: 99%

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

Maio

Rosa

Pelucchi

et al. 2022

IJMS

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Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson’s and Alzheimer’s disease. Interestingly, also in Parkinson’s disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.

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Presynaptic bouton compartmentalization and postsynaptic density-mediated glutamate receptor clustering via phase separation

Cited by 11 publications

References 133 publications

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

Coupling Bulk Phase Separation of Disordered Proteins to Membrane Domain Formation in Molecular Simulations on a Bespoke Compute Fabric

Postsynaptic protein assembly in three- and two-dimensions studied by mesoscopic simulations

Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson’s and Alzheimer’s Disease Patients

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