The Experts below are selected from a list of 17583 Experts worldwide ranked by ideXlab platform
Nicolas L. Fawzi - One of the best experts on this subject based on the ideXlab platform.
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Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Yelena Kan, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp^2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
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molecular interactions underlying liquid liquid phase separation of the FUS low complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
Sapun H. Parekh - One of the best experts on this subject based on the ideXlab platform.
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Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Yelena Kan, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp^2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
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molecular interactions underlying liquid liquid phase separation of the FUS low complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
Gül H. Zerze - One of the best experts on this subject based on the ideXlab platform.
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Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Yelena Kan, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp^2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
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molecular interactions underlying liquid liquid phase separation of the FUS low complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
Anastasia C. Murthy - One of the best experts on this subject based on the ideXlab platform.
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Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Yelena Kan, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp^2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
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molecular interactions underlying liquid liquid phase separation of the FUS low complexity domain
Nature Structural & Molecular Biology, 2019Co-Authors: Anastasia C. Murthy, Gregory L. Dignon, Gül H. Zerze, Sapun H. Parekh, Jeetain Mittal, Nicolas L. FawziAbstract:The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
Alessandro Rosa - One of the best experts on this subject based on the ideXlab platform.
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FUS ALS-causative mutations impact FUS autoregulation and the processing of RNA-binding proteins through intron retention
bioRxiv, 2019Co-Authors: Jack Humphrey, Nicol Birsa, Carmelo Milioto, David Robaldo, Matthew Bentham, Seth Jarvis, Cristian Bodo, Maria Giovanna Garone, Anny Devoy, Alessandro RosaAbstract:Mutations in the RNA binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS has been established to have a role in numerous aspects of RNA processing, including splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.
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FUS affects circular rna expression in murine embryonic stem cell derived motor neurons
Nature Communications, 2017Co-Authors: Alessandro Rosa, Lorenzo Errichelli, Stefano Dini Modigliani, Pietro Laneve, Alessio Colantoni, Ivano Legnini, Davide CapautoAbstract:The RNA-binding protein FUS participates in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA (circRNA) production. We identified circRNAs expressed in in vitro-derived mouse motor neurons (MNs) and determined that the production of a considerable number of these circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-associated FUS mutants, we directly correlate the modulation of circRNA biogenesis with alteration of FUS nuclear levels and with putative toxic gain of function activities. We also demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the back-splicing junctions and that this control can be reproduced with artificial constructs. Most circRNAs are conserved in humans and specific ones are deregulated in human-induced pluripotent stem cell-derived MNs carrying the FUSP525L mutation associated with ALS. The RNA binding protein FUS functions in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). Here the authors show that FUS controls back-splicing reactions leading to circular RNA (circRNA) production in stem cell-derived motor neurons and that ALS-associated FUS mutations affect the biogenesis of circRNAs.
