scholarly journals SynGAP isoforms differentially regulate synaptic plasticity and dendritic development

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yoichi Araki ◽  
Ingie Hong ◽  
Timothy R Gamache ◽  
Shaowen Ju ◽  
Leonardo Collado-Torres ◽  
...  
Keyword(s):  
Phase Separation ◽  
Splice Variants ◽  
Expression Patterns ◽  
Cognitive Disorders ◽  
Biochemical Properties ◽  
Pdz Domains ◽  
Synaptic Targeting ◽  
Spatiotemporal Expression ◽  
Dendritic Development ◽  
Liquid Liquid Phase Separation

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. Although studies have implicated SYNGAP1 in several cognitive disorders, it is not clear which SynGAP isoforms contribute to disease. Here, we demonstrate that SynGAP isoforms exhibit unique spatiotemporal expression patterns and play distinct roles in neuronal and synaptic development in mouse neurons. SynGAP-α1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-β, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-α1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-β. These results demonstrate that distinct intrinsic biochemical properties of SynGAP isoforms determine their function, and individual isoforms may differentially contribute to the pathogenesis of SYNGAP1-related cognitive disorders.

scholarly journals SynGAP splice isoforms differentially regulate synaptic plasticity and dendritic development

2020 ◽  
Author(s):  
Yoichi Araki ◽  
Ingie Hong ◽  
Timothy R. Gamache ◽  
Shaowen Ju ◽  
Leonardo Collado-Torres ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Splice Variants ◽  
Liquid Phase Separation ◽  
Synaptic Activity ◽  
List Type ◽  
Synaptic Targeting ◽  
Spatiotemporal Expression ◽  
Dendritic Development ◽  
Liquid Liquid Phase Separation

SummarySynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. Although recent studies have implicated SYNGAP1 haploinsufficiency in ID/ASD pathogenesis, the degree to which each SynGAP isoform contributes to disease pathogenesis remains elusive. Here we demonstrate that individual SynGAP isoforms exhibit unique spatiotemporal expression and have distinct roles in neuronal and synaptic development. The SynGAP-α1 isoform, which undergoes robust liquid-liquid phase-separation with PSD-95 and is highly-enriched in synapses, is expressed late in development and disperses from synaptic spines in response to LTP-inducing synaptic activity to allow for AMPA receptor insertion and spine enlargement. In contrast, the SynGAP-β isoform, which undergoes less liquid-liquid phase-separation with PSD95 and is less synaptically targeted, is expressed early in development and promotes dendritic arborization. Interestingly, a SynGAP-α1 mutation that disrupts phase separation and synaptic targeting abolishes its function in plasticity and instead drives dendritic arbor development like the β isoform. These results demonstrate that distinct phase separation and synaptic targeting properties of SynGAP isoforms determine their function.HighlightsSynGAP-α1, α2, β, γ isoforms have distinct spatiotemporal expression and function in the brain.SynGAP-α1 is required for plasticity, while β is required for dendritic development.Liquid-liquid phase separation of SynGAP-α1 is required for its role in plasticity.SynGAP isoforms may differentially contribute to SYNGAP1 related human NDDs.

scholarly journals Programmable Sequences of Reflectin Proteins Provides Evidence for Their Evolution Processes, Tunable Intracellular Localization and Interaction with Cytoskeleton

2021 ◽  
Author(s):  
Junyi Song ◽  
Liu Chuanyang ◽  
Baoshan Li ◽  
Liangcheng Liu ◽  
LIng Zeng ◽  
...  
Keyword(s):  
Phase Separation ◽  
Spatial Organization ◽  
Dynamic Performance ◽  
Intracellular Localization ◽  
Evolutionary Relationship ◽  
Biochemical Properties ◽  
Membrane Bound ◽  
Phase Out ◽  
Intracellular Milieu ◽  
Liquid Liquid Phase Separation

Reflectins are membrane-bound proteins located in cephalopods iridocytes, with repeated canonical domains interspersed with cationic linkers. Scientists keep curious about their evolutionary processes, biochemical properties and intracellular functions. Here, by introducing reflectin A1, A2, B1 and C into HEK-293T cells, these proteins were found to phase out from the crowded intracellular milieu, with distinguished localization preferences. Inspired by their programmable block sequences, several truncated reflectin A1 (RfA1) peptides based on repetition of reflectin motifs were designed and transfected into cells. An obvious cyto-/nucleo-plasmic localization preference was once again observed. The dynamic performance of RfA1 derivatives and their analogic behavior between different reflectins suggest a conceivable evolutionary relationship among reflectin proteins. Additionally, a proteomic survey identified biochemical partners which contribute to the phase separation and intracellular localization of RfA1 and its truncations, as well as the close collaboration between RfA1 and the cytoskeleton systems. These findings indicate that liquid-liquid phase separation could be the fundamental mode for reflectins to achieve spatial organization, to cooperate with cytoskeleton during the regulation of reflective coloration. On the other hand, the dynamic behaviors of RfA1 derivatives strongly recommended themselves as programmable molecular tools.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

scholarly journals Does liquid–liquid phase separation drive peptide folding?

2021 ◽  
Author(s):  
Dean N. Edun ◽  
Meredith R. Flanagan ◽  
Arnaldo L. Serrano
Keyword(s):  
Infrared Spectroscopy ◽  
Phase Separation ◽  
Liquid Phase ◽  
Model Membrane ◽  
Peptide Folding ◽  
Two Dimensional ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Peptide ◽  
Two Dimensional Infrared Spectroscopy ◽  
Liquid Liquid Phase Separation

Two-dimensional infrared spectroscopy reveals folding of an intrinsically disordered peptide when sequestered into a model “membrane-less” organelle.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Deciphering the Role of π-Interactions in Polyelectrolyte Complexes Using Rationally Designed Peptides

Polymers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 2074
Author(s):  
Sara Tabandeh ◽  
Cristina Elisabeth Lemus ◽  
Lorraine Leon
Keyword(s):  
Hydrogen Bonding ◽  
Phase Separation ◽  
Liquid Phase ◽  
Charge Density ◽  
Secondary Structures ◽  
Liquid Phase Separation ◽  
Polyelectrolyte Complexes ◽  
Π Interactions ◽  
Liquid Liquid Phase Separation

Electrostatic interactions, and specifically π-interactions play a significant role in the liquid-liquid phase separation of proteins and formation of membraneless organelles/or biological condensates. Sequence patterning of peptides allows creating protein-like structures and controlling the chemistry and interactions of the mimetic molecules. A library of oppositely charged polypeptides was designed and synthesized to investigate the role of π-interactions on phase separation and secondary structures of polyelectrolyte complexes. Phenylalanine was chosen as the π-containing residue and was used together with lysine or glutamic acid in the design of positively or negatively charged sequences. The effect of charge density and also the substitution of fluorine on the phenylalanine ring, known to disrupt π-interactions, were investigated. Characterization analysis using MALDI-TOF mass spectroscopy, H NMR, and circular dichroism (CD) confirmed the molecular structure and chiral pattern of peptide sequences. Despite an alternating sequence of chirality previously shown to promote liquid-liquid phase separation, complexes appeared as solid precipitates, suggesting strong interactions between the sequence pairs. The secondary structures of sequence pairs showed the formation of hydrogen-bonded structures with a β-sheet signal in FTIR spectroscopy. The presence of fluorine decreased hydrogen bonding due to its inhibitory effect on π-interactions. π-interactions resulted in enhanced stability of complexes against salt, and higher critical salt concentrations for complexes with more π-containing amino acids. Furthermore, UV-vis spectroscopy showed that sequences containing π-interactions and increased charge density encapsulated a small charged molecule with π-bonds with high efficiency. These findings highlight the interplay between ionic, hydrophobic, hydrogen bonding, and π-interactions in polyelectrolyte complex formation and enhance our understanding of phase separation phenomena in protein-like structures.

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