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Role of Disordered Regions in RNA-Binding Proteins for Function and Pathology

Applicant Schuler Benjamin
Number 170976
Funding scheme Sinergia
Research institution Biochemisches Institut Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Interdisciplinary
Start/End 01.01.2017 - 31.03.2021
Approved amount 2'599'530.00
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All Disciplines (5)

Discipline
Interdisciplinary
Biochemistry
Biophysics
Physical Chemistry
Cellular Biology, Cytology

Keywords (8)

EPR; Single-molecule spectroscopy; Intrinsically disordered regions; Cell biology; Phase separation; NMR; RNA-binding proteins; Molecular pathogenesis

Lay Summary (German)

Lead
Der Einfluss unstrukturierter Bereiche in RNA-bindenen Proteinen auf Funktion und Pathologie
Lay summary

Proteine sind die wichtigsten molekularen Maschinen in unserem Körper. Das traditionelle Bild von Proteinen ist geprägt durch die wichtige Erkenntnis, dass Proteine für viele Funktionen eine wohlgeordnete ('gefaltete') dreidimensionale Struktur benötigen. Neuere Erkenntnisse zeigen allerdings, dass ein überraschend grosser Anteil von Proteinen in höheren Eukaryonten substantielle Anteile enthalten, die auch unter physiologischen Bedingungen unstrukturiert vorliegen, oder sogar ganz unstrukturiert sind. Dennoch sind sie offenbar von entscheidender Bedeutung für die Funktion der Zelle. Besonders häufig kommen solche unstrukturierten Bereiche in Proteinen vor, die an der Bindung und Prozessierung von RNA beteiligt sind, aber ihr funktioneller Einfluss und ihre Rolle in der Entwicklung von Krankheiten ist weitgehend unbekannt.

In dieser interdisziplinären Zusammenarbeit werden die Eigenschaften von unstrukturierten Bereichen in RNA-bindenden Proteinen und ihre Bedeutung für Proteinfunktion und Krankheitsentwicklung untersucht. Durch eine Kombination von Methoden aus Pathologie, Zellbiologie, Biochemie, Biophysik und Physikalischer Chemie, die ideal für diese Fragestellung geeignet sind, aber in dieser Form selten kombiniert werden können, da sie hochspezialisiertes Wissen erfordern, werden die Synergien am Standort Zürich optimal genutzt.

Spezifische Ziele des Projekts sind es, diese Methoden für die Fragestellung weiterzuentwickeln, die Flexibilität und Strukturverteilungen der Moleküle zu quantifizieren, den Einfluss unstrukturierter Bereiche auf die zelluläre Funktion zu verstehen, ihre Rolle für das Phänomen zellulärer Phasenseparation einzuordnen, und die weitere Entwicklung pathogener Ablagerungen zu charakterisieren, die bei vielen neurodegenerativen Krankheiten auftreten.

Direct link to Lay Summary Last update: 01.12.2016

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Depletion interactions modulate the binding between disordered proteins in crowded environments
Zosel Franziska, Soranno Andrea, Buholzer Karin J., Nettels Daniel, Schuler Benjamin (2020), Depletion interactions modulate the binding between disordered proteins in crowded environments, in Proceedings of the National Academy of Sciences, 117(24), 13480-13489.
A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction
Zosel Franziska, Mercadante Davide, Nettels Daniel, Schuler Benjamin (2018), A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction, in Nature Communications, 9(1), 3332-3332.
Dispersion Correction Alleviates Dye Stacking of Single-Stranded DNA and RNA in Simulations of Single-Molecule Fluorescence Experiments
Grotz Kara K., Nueesch Mark F., Holmstrom Erik D., Heinz Marcel, Stelzl Lukas S., Schuler Benjamin, Hummer Gerhard (2018), Dispersion Correction Alleviates Dye Stacking of Single-Stranded DNA and RNA in Simulations of Single-Molecule Fluorescence Experiments, in The Journal of Physical Chemistry B, 122(49), 11626-11639.
Conformational Plasticity of Hepatitis C Virus Core Protein Enables RNA-Induced Formation of Nucleocapsid-like Particles
Holmstrom Erik D., Nettels Daniel, Schuler Benjamin (2018), Conformational Plasticity of Hepatitis C Virus Core Protein Enables RNA-Induced Formation of Nucleocapsid-like Particles, in Journal of Molecular Biology, 430(16), 2453-2467.
Accurate Transfer Efficiencies, Distance Distributions, and Ensembles of Unfolded and Intrinsically Disordered Proteins From Single-Molecule FRET
Holmstrom Erik D., Holla Andrea, Zheng Wenwei, Nettels Daniel, Best Robert B., Schuler Benjamin (2018), Accurate Transfer Efficiencies, Distance Distributions, and Ensembles of Unfolded and Intrinsically Disordered Proteins From Single-Molecule FRET, in Cruzer Zoe (ed.), Elsevier, USA, 287-325.
Combining short- and long-range fluorescence reporters with simulations to explore the intramolecular dynamics of an intrinsically disordered protein
Zosel Franziska, Haenni Dominik, Soranno Andrea, Nettels Daniel, Schuler Benjamin (2017), Combining short- and long-range fluorescence reporters with simulations to explore the intramolecular dynamics of an intrinsically disordered protein, in The Journal of Chemical Physics, 147(15), 152708-152708.
Structural Biology outside the box — inside the cell
Plitzko Jürgen M, Schuler Benjamin, Selenko Philipp (2017), Structural Biology outside the box — inside the cell, in Current Opinion in Structural Biology, 46, 110-121.
Labeling of proteins for single-molecule fluorescence spectroscopy
ZoselFranziska, HollaAndrea, SchulerBenjamin, Labeling of proteins for single-molecule fluorescence spectroscopy, Springer, Ney York.

Datasets

Macromolecular Structure

Author Masliah, Gregoire
Publication date 21.02.2018
Persistent Identifier (PID) https://www.rcsb.org/structure/5N8M
Repository RCSB Protein Data Bank
Abstract
The accurate cleavage of pre-micro(mi)RNAs by Dicer and mi/siRNA guide strand selection are important steps in forming the RNA-induced silencing complex (RISC). The role of Dicer binding partner TRBP in these processes remains poorly understood. Here, we solved the solution structure of the two N-terminal dsRNA binding domains (dsRBDs) of TRBP in complex with a functionally asymmetric siRNA using NMR, EPR, and single-molecule spectroscopy. We find that siRNA recognition by the dsRBDs is not sequence-specific but rather depends on the RNA shape. The two dsRBDs can swap their binding sites, giving rise to two equally populated, pseudo-symmetrical complexes, showing that TRBP is not a primary sensor of siRNA asymmetry. Using our structure to model a Dicer-TRBP-siRNA ternary complex, we show that TRBP's dsRBDs and Dicer's RNase III domains bind a canonical 19 base pair siRNA on opposite sides, supporting a mechanism whereby TRBP influences Dicer-mediated cleavage accuracy by binding the dsRNA region of the pre-miRNA during Dicer cleavage.

Macromolecular Structure

Author Masliah, Gregoire
Publication date 21.02.2018
Persistent Identifier (PID) https://www.rcsb.org/structure/5N8L
Repository RCSB Protein Data Bank
Abstract
The accurate cleavage of pre-micro(mi)RNAs by Dicer and mi/siRNA guide strand selection are important steps in forming the RNA-induced silencing complex (RISC). The role of Dicer binding partner TRBP in these processes remains poorly understood. Here, we solved the solution structure of the two N-terminal dsRNA binding domains (dsRBDs) of TRBP in complex with a functionally asymmetric siRNA using NMR, EPR, and single-molecule spectroscopy. We find that siRNA recognition by the dsRBDs is not sequence-specific but rather depends on the RNA shape. The two dsRBDs can swap their binding sites, giving rise to two equally populated, pseudo-symmetrical complexes, showing that TRBP is not a primary sensor of siRNA asymmetry. Using our structure to model a Dicer-TRBP-siRNA ternary complex, we show that TRBP's dsRBDs and Dicer's RNase III domains bind a canonical 19 base pair siRNA on opposite sides, supporting a mechanism whereby TRBP influences Dicer-mediated cleavage accuracy by binding the dsRNA region of the pre-miRNA during Dicer cleavage.

Collaboration

Group / person Country
Types of collaboration
Ruedi Aebersold Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Paolo Paganetti Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Gerhard Hummer Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dmitrii Makarov United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
54th Annual International Meeting of the ESR Spectroscopy Group of the Royal Society of Chemistry Talk given at a conference Ensemble modelling of intrinsically disordered protein domains with EPR-derived distance distributions: The case of hnRNP A1. 12.04.2021 Cardiff, Great Britain and Northern Ireland Jeschke Gunnar;
54th Annual International Meeting of the ESR Spectroscopy Group of the Royal Society of Chemistry Talk given at a conference Resolving small distance variations by single-molecule FRET & EPR spectroscopy using rotamer libraries. 12.04.2021 Cardiff, Great Britain and Northern Ireland Klose Daniel;
IDP Annual Meeting ELIXIR (online) Talk given at a conference Single-Molecule FRET of Intrinsically Disordered Proteins 23.02.2021 online (unbekannt), Switzerland Schuler Benjamin;
Seminar, Center for Physics in Living Cells, University of Illinois (online) Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 14.12.2020 Urbana-Champaign , United States of America Schuler Benjamin;
Mößbauer-Seminar, Max Planck Institute for Biomedical Research (online) Talk given at a conference Single-molecule spectroscopy of protein interactions: Binding without folding 02.11.2020 Heidelberg, Germany Schuler Benjamin;
Magnetic Resonances Meet the Future of Biophysics Talk given at a conference Characterization of the Role of the Inter-RRM Linker of SRSF1 with EPR spectroscopy 25.09.2020 Rockville / Online, United States of America Esteban Hofer Laura;
Single Molecule Biophysics Les Houches 2020 Talk given at a conference Probing the dynamics and interaction mechanisms of disordered proteins with single-molecule spectroscopy 03.02.2020 Les Houches, France Schuler Benjamin;
14th NMR Winter Retreat of Protein-RNA Interactions Talk given at a conference Investigation of the function of SRSF1 disordered regions in RNA binding and droplet formation 12.01.2020 Parpan, Switzerland Nguyen Cristina Kim Xuan; Esteban Hofer Laura;
Seminar, St. Jude Children’s Research Hospital, Department of Biochemistry Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 10.01.2020 Memphis, TN, United States of America Schuler Benjamin;
Gordon Research Conference Protein Folding Dynamics Talk given at a conference Single-Molecule Spectroscopy of Disordered Proteins: Dynamics, Function, and (Sometimes) Folding 05.01.2020 Galveston, TX, United States of America Schuler Benjamin;
8th EFEPR School Poster Characterization of the role of the flexible linker of SRSF1 with EPR spectroscopy 18.11.2019 Brno, Czech Republic Esteban Hofer Laura;
Functional dynamics – visualizing molecules in action, Nature Conference, Biodesign Institute, Arizona State University Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 08.11.2019 Phoenix, United States of America Schuler Benjamin;
Seminar, Center for Biological Physics, Arizona State University Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 06.11.2019 Phoenix, United States of America Schuler Benjamin;
Seminar, Department of Biomedical Engineering, Washington University in St. Louis, Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 01.11.2019 St. Louis, MO, United States of America Schuler Benjamin;
Physics Meets Biology 2019 Talk given at a conference Keynote Lecture, Biological Polyelectrolytes: Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 10.09.2019 Oxford, Great Britain and Northern Ireland Schuler Benjamin;
25th International Anniversary Workshop on “Single Molecule Spectroscopy and Super-resolution Microscopy in the Life Sciences”, Talk given at a conference Probing Intrinsically Disordered Proteins and Their Interaction Mechanisms With Single-Molecule Spectroscopy 05.09.2019 Berlin, Germany Schuler Benjamin;
Workshop Deciphering Complex Energy Landscape and Kinetic Networks from Single Molecules to Cells Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 05.09.2019 Dijon, France Schuler Benjamin;
13th Symposium on Trends in Structural Biology Talk given at a conference Session chair, Single-molecule spectroscopy 19.08.2019 Zürich, Switzerland Schuler Benjamin;
Joint 12th EBSA European Biophysics Congress / 10th IUPAP International Conference on Biological Physics (ICBP) Poster Characterization of liquid-liquid phase separation of FUS with EPR spectroscopy 20.07.2019 Madrid, Spain Jeschke Gunnar; Allain Frédéric; Emmanouilidis Leonidas; Esteban Hofer Laura;
TSRC Workshop on Macromolecular Crowding Talk given at a conference Depletion interactions modulate coupled folding and binding in crowded environments 17.07.2019 Telluride, Colorado, United States of America Schuler Benjamin;
TSRC Workshop on Intrinsically Disordered Proteins Talk given at a conference Properties and functions of biological polyelectrolyte complexes 16.07.2019 Telluride, Colorado, United States of America Schuler Benjamin;
The Wonderful Polypeptide Universe: From Dynamic Chains to Macromolecular Assemblies, Symposium Talk given at a conference From many to single molecules (and back) 10.05.2019 Potsdam, Germany Schuler Benjamin;
The 52nd Annual International Meeting of the ESR Spectroscopy Group of the Royal Society of Chemistry Talk given at a conference Methodology development for the characterization of liquid-liquid phase separation of FUS with EPR spectroscopy 07.04.2019 Scotland, Great Britain and Northern Ireland Esteban Hofer Laura;
63rd Annual Meeting of the Biophysical Society Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 03.03.2019 Baltimore, United States of America Schuler Benjamin;
Seminar, Laboratory of Chemical Physics, NIH Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 28.02.2019 Bethesta, United States of America Schuler Benjamin;
Seminar, Institut Fresnel Talk given at a conference Nanosecond FCS: Probing sub-microsecond biomolecular dynamics 01.02.2019 Marseille, France Schuler Benjamin;
Seminar, CNRS & Aix Marseille University Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 01.02.2019 Montpellier, France Schuler Benjamin;
Seminar, Institut Fresnel Talk given at a conference Nanosecond FCS: Probing sub-microsecond biomolecular dynamics 01.02.2019 Marseille, France Schuler Benjamin;
Seminar, CNRS & Aix Marseille University, Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 01.02.2019 Marseille, France Schuler Benjamin;
Seminar, Centre de Biochimie Structurale, CNRS Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 31.01.2019 Montpellier, France Schuler Benjamin;
Seminar, Centre de Biochimie Structurale, CNRS Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 31.01.2019 Montpellier, France Schuler Benjamin;
13th NMR Winter Retreat of Protein-RNA Interactions Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 14.01.2019 Parpan, Switzerland Schuler Benjamin;
13th NMR Winter Retreat of Protein-RNA Interactions Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 14.01.2019 Parpan, Switzerland Schuler Benjamin;
6th European Workshop on Advanced Fluorescence Methods Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins 11.12.2018 München, Germany Schuler Benjamin;
6th European Workshop on Advanced Fluorescence Methods Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins 11.12.2018 München, Germany Schuler Benjamin;
Linderstrøm-Lang Symposium, Current topics in Protein Chemistry Talk given at a conference Single-Molecule Spectroscopy of Protein Order and Disorder 16.11.2018 Kopenhagen, Denmark Schuler Benjamin;
Linderstrøm-Lang Symposium, Current topics in Protein Chemistry Talk given at a conference Single-Molecule Spectroscopy of Protein Order and Disorder 16.11.2018 Kopenhagen, Denmark Schuler Benjamin;
Seminar, Center for Molecular and Cellular Bioengineering Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 25.10.2018 Dresden, Germany Schuler Benjamin;
Seminar, Center for Molecular and Cellular Bioengineering Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 25.10.2018 Dresden, Germany Schuler Benjamin;
GBM biannual Murnau Conference, New Frontiers in Structural Biology, Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 27.09.2018 Bavaria, Germany Schuler Benjamin;
GBM biannual Murnau Conference, New Frontiers in Structural Biology Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 27.09.2018 Bavaria, Switzerland Schuler Benjamin;
Summer School, Micro and Optical Technologies in Biomedical Science Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins 12.09.2018 Fiesch, Switzerland Schuler Benjamin;
Summer School, Micro and Optical Technologies in Biomedical Science Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins 12.09.2018 Fiesch, Switzerland Schuler Benjamin;
27th PicoQuant Single Molecule Workshop: Single Molecule Spectroscopy and Super-resolution Microscopy in the Life Sciences Talk given at a conference Conformational Dimensions and Dynamics of Homopolymeric Single-stranded Nucleic Acids 12.09.2018 Berlin, Germany Schuler Benjamin;
Seminar, University of Aarhus Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 07.09.2018 Aarhus, Denmark Schuler Benjamin;
Seminar, University of Aarhus Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 07.09.2018 Aarhus, Denmark Schuler Benjamin;
7th EuCheMS Chemistry Congress, Molecular frontiers & global challenges Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 29.08.2018 Liverpool, Great Britain and Northern Ireland Schuler Benjamin;
7th EuCheMS Chemistry Congress, Molecular frontiers & global challenges, ACC Liverpool Talk given at a conference Single-Molecule Spectroscopy of Intrinsically Disordered Proteins and Their Interaction Mechanisms 29.08.2018 Liverpool, Great Britain and Northern Ireland Schuler Benjamin;
14th Greta Pifat Mrzljak International School of Biophysics Poster Studies of the disordered regions of FUS and SRSF1 with EPR 23.08.2018 Split, Croatia Esteban Hofer Laura; Allain Frédéric; Nguyen Cristina Kim Xuan; Emmanouilidis Leonidas; Jeschke Gunnar;
14th International School of Biophysics Poster Studies of the disordered regions of FUS and SRFS1 with EPR 23.08.2018 Split, Croatia Esteban Hofer Laura;
XXVIII ICMRBS Talk given at a conference Rigid or flexible or rather in between – What distance distributions tell on ensemble width 19.08.2018 Dublin, Ireland Jeschke Gunnar;
Gordon Research Conference: Single Molecule Approaches to Biology Poster Conformational Dimensions and Dynamics of Unstructured Single-Stranded Nucleic Acids 15.07.2018 Mount Snow , United States of America Holmstrom Erik D.;
Gordon Research Conference, Intrinsically Disordered Proteins Talk given at a conference Highly Disordered Biomolecular Complexes 02.07.2018 Les Diablerets, Switzerland Schuler Benjamin;
Gordon Research Conference, Intrinsically Disordered Proteins Talk given at a conference Highly Disordered Biomolecular Complexes 02.07.2018 Les Diablerets, Switzerland Schuler Benjamin;
Seminar, University of Cambridge Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 24.06.2018 Cambridge, Great Britain and Northern Ireland Schuler Benjamin;
Seminar, University of Cambridge, Cambridge Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 24.06.2018 Cambridge, Great Britain and Northern Ireland Schuler Benjamin;
Workshop, Dynamics of Biological Macromolecules Talk given at a conference Dynamics and interactions of disordered proteins from single-molecule spectroscopy 04.06.2018 Lund, Sweden Schuler Benjamin;
Workshop, Dynamics of Biological Macromolecules, Lund University Talk given at a conference Dynamics and interactions of disordered proteins from single-molecule spectroscopy 04.06.2018 Lund, Sweden Schuler Benjamin;
TSRC Workshop, Protein Dynamics, Les Houches School of Physics Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 30.05.2018 Les Houches, France Schuler Benjamin;
TSRC Workshop, Protein Dynamics Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 30.05.2018 Les Houches School of Physics, Les Houches, France Schuler Benjamin;
Workshop, Protein Science in Human Diseases Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 25.05.2018 Parma, Italy Schuler Benjamin;
Workshop, Protein Science in Human Diseases, University of Parma Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 25.05.2018 Parma, Italy Schuler Benjamin;
Spring Conference, Conformational Transitions in Proteins Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 04.05.2018 Venedig, Italy Schuler Benjamin;
Spring Conference, Conformational Transitions in Proteins Talk given at a conference Binding without folding: Extreme disorder and dynamics in a high-affinity protein complex 04.05.2018 Venedig, Italy Schuler Benjamin;
Brandeis University Faculty Interview Individual talk Macromolecular Structural Dynamics: A View Through the Lens of a Single Molecule Microscope 15.02.2018 Waltham MA, United States of America Holmstrom Erik D.;
University of Kansas Faculty Interview Individual talk Macromolecular Structural Dynamics: A View Through the Lens of a Single Molecule Microscope 30.01.2018 Lawrence-Kansas, United States of America Holmstrom Erik D.;
CECAM-Lorentz Joint Workshop, Multiscale-modelling of nucleosomes and their positioning on DNA Talk given at a conference A biological polyelectrolyte complex in histone H1 chaperoning 15.01.2018 Lausanne, Switzerland Schuler Benjamin;
CECAM-Lorentz Joint Workshop, Multiscale-modelling of nucleosomes and their positioning on DNA Talk given at a conference A biological polyelectrolyte complex in histone H1 chaperoning 15.01.2018 Lausanne, Switzerland Schuler Benjamin;
Gordon Research Seminar/Gordon Research Conference on Protein Folding Dynamics Talk given at a conference A proline switch explains conformational and kinetic heterogeneity in the interaction between two intrinsically disordered proteins 08.01.2018 Galveston, Texas, United States of America Zosel Franziska;
Seminar, Department of Physical Chemistry, University of Basel Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 29.11.2017 Basel, Switzerland Schuler Benjamin;
Seminar, Department of Physical Chemistry, University of Basel Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 29.11.2017 Basel, Switzerland Schuler Benjamin;
Seminar, Weizmann Institute of Science Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 14.11.2017 Rehovot, Israel Schuler Benjamin;
Seminar, Weizmann Institute of Science Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 14.11.2017 Rehovot, Israel Schuler Benjamin;
3rd FCS Workshop 2017 Fluorescence Correlation Spectroscopy in Soft Matter Science, Talk given at a conference Single-molecule spectroscopy and FCS of intrinsically disordered proteins 12.10.2017 München, Germany Schuler Benjamin;
Probing the Structure, Dynamics, and Function of Disordered Proteins with Single-molecule Spectroscopy Talk given at a conference Single-molecule spectroscopy and FCS of intrinsically disordered proteins 12.10.2017 München, Germany Schuler Benjamin;
Third Infinity Conference Talk given at a conference Probing the Structure, Dynamics, and Function of Disordered Proteins with Single-molecule Spectroscopy 09.10.2017 Göttingen, Germany Schuler Benjamin;
Third Infinity Conference Talk given at a conference Probing the Structure, Dynamics, and Function of Disordered Proteins with Single-molecule Spectroscopy 09.10.2017 Göttingen, Germany Schuler Benjamin;
CECAM Workshop "Disordered protein segments: revisiting the structure-function paradigm" Talk given at a conference A proline switch explains conformational and kinetic heterogeneity in an IDP interaction 05.10.2017 Paris, France Zosel Franziska;
University College London Faculty Interview Individual talk Single-molecule single-cell virology: a mechanistic approach to understanding the function of viral nucleoproteins 21.09.2017 London, Great Britain and Northern Ireland Holmstrom Erik D.;
23rd PicoQuant Single Molecule Workshop: Single Molecule Spectroscopy and Super-resolution Microscopy in the Life Sciences Talk given at a conference Using single-molecule FRET to study the structure and function of an intrinsically disordered nucleic acid chaperone 13.09.2017 Berlin, Germany Holmstrom Erik D.;
Workshop Deciphering Complex Energy Landscape and Kinetic Networks from Single Molecules to Cells Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 07.09.2017 Dijon, France Schuler Benjamin;
Symposium Protein Folding, Evolution and Interaction Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 05.09.2017 Cambridge, Great Britain and Northern Ireland Schuler Benjamin;
Symposium Protein Folding, Evolution and Interaction Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 05.09.2017 Cambridge, Great Britain and Northern Ireland Schuler Benjamin;
3rd Symposium on Non-Globular Proteins Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 31.08.2017 Kosice, Slovakia Schuler Benjamin;
3rd Symposium on Non-Globular Proteins (NPG-Net) Talk given at a conference Binding without folding: Extreme disorder in a high-affinity protein complex 31.07.2017 Kosice, Slovakia Schuler Benjamin;
19th IUPAB and 11th EBSA Biophysics Congress Talk given at a conference Single-molecule spectroscopy of folding and assembly of the cytolytic pore toxin ClyA 18.07.2017 Edinburgh, Great Britain and Northern Ireland Schuler Benjamin;
19th IUPAB and 11th EBSA Biophysics Congress Talk given at a conference Single-molecule spectroscopy of folding and assembly of the cytolytic pore toxin ClyA 18.07.2017 Edinburgh, Great Britain and Northern Ireland Schuler Benjamin;
19th IUPAB Congress / 11th EBSA Congress Poster Rotamer Libraries of spin and fluorescence labels aid structural interpretation of experimental data 16.07.2017 Edinbutgh, Great Britain and Northern Ireland Jeschke Gunnar; Klose Daniel;
Telluride Science Research Center (TSRC) Workshop How conformational landscapes control intra- and inter-molecular interactions of IDPs Talk given at a conference Extreme disorder in a high-affinity protein complex 14.07.2017 Telluride, CO, United States of America Schuler Benjamin;
Telluride Science Research Center (TSRC) Workshop How conformational landscapes control intra- and inter-molecular interactions of IDPs Talk given at a conference Extreme disorder in a high-affinity protein complex 14.07.2017 Telluride, United States of America Schuler Benjamin;
Telluride Science Research Center (TSRC) Workshops How conformational landscapes control intra- and inter-molecular interactions of IDPs and Designing Biomolecular Switches Talk given at a conference Single-Molecule Spectroscopy of Protein Disorder 13.07.2017 Telluride, United States of America Schuler Benjamin;
Telluride Science Research Center (TSRC) Workshops How conformational landscapes control intra- and inter-molecular interactions of IDPs and Designing Biomolecular Switches Talk given at a conference Single-Molecule Spectroscopy of Protein Disorder 13.07.2017 Telluride, CO, United States of America Schuler Benjamin;
Symposium Joining Forces -- Protein Aggregation in Health and Disease, ETH Zurich Talk given at a conference Binding without folding in a highly disordered protein complex 20.06.2017 Zürich, Switzerland Schuler Benjamin;
Symposium Joining Forces -- Protein Aggregation in Health and Disease Talk given at a conference Binding without folding in a highly disordered protein complex 20.06.2017 Zürich ETH, Switzerland Schuler Benjamin;
Seminar, Institut des sciences et ingénierie chimiques, EPFL Talk given at a conference Binding without folding in a highly disordered protein complex 07.04.2017 Lausanne, Switzerland Schuler Benjamin;
Seminar, Institut des sciences et ingénierie chimiques, EPFL Talk given at a conference Binding without folding in a highly disordered protein complex 07.04.2017 Lausanne, Switzerland Schuler Benjamin;
Weizmann Institut of Science, Department of Structural Biology Seminar Series Talk given at a conference Dynamics and Interactions of Intrinsically Disordered Proteins Probed with Single-molecule Spectroscopy 28.03.2017 Rehovot, Israel Zosel Franziska;
Biophysical Society 61st Annual Meeting Talk given at a conference Depletion effects control the binding and folding of two intrinsically disordered proteins in crowded environments 11.02.2017 New Orleans, United States of America Zosel Franziska;
12th Symposium Trends in Structural Biology Talk given at a conference Dynamics and Interactions of Intrinsically Disordered Proteins Probed with Single-molecule Spectroscopy 07.02.2017 Zürich, Switzerland Zosel Franziska;
Tri-Institutional Structural Biology Seminar Individual talk Single-Molecule Spectroscopy of Unfolded and Intrinsically Disordered Proteins 17.01.2017 New York, United States of America Schuler Benjamin;
Tri-Institutional Structural Biology Seminar Talk given at a conference Single-Molecule Spectroscopy of Unfolded and Intrinsically Disordered Proteins 17.01.2017 New York USA, United States of America Schuler Benjamin;
Gordon Research Conference Stochastic Physics in Biology Talk given at a conference Dynamics of Unfolded and Intrinsically Disordered Proteins from Single-Molecule Spectroscopy 09.01.2017 Ventura, CA, United States of America Schuler Benjamin;
Gordon Research Conference Stochastic Physics in Biology Talk given at a conference Dynamics of Unfolded and Intrinsically Disordered Proteins from Single-Molecule Spectroscopy 09.01.2017 Ventura CA, United States of America Schuler Benjamin;


Associated projects

Number Title Start Funding scheme
157034 Nanometer-range distance constraints for biomolecular complexes - Measurement, uncertainty estimates, and use in modeling 01.10.2014 Project funding (Div. I-III)
144862 Deciphering the mechanisms of TDP-43 and FUS/TLS mediated neurotoxicity 01.09.2013 SNSF Professorships
198476 Imaging heterogeneous TDP-43 neuropathologies 01.07.2021 Joint Programming
152839 Probing interaction mechanisms of intrinsically disordered proteins with single-molecule spectroscopy 01.04.2014 Project funding (Div. I-III)
188467 New types of information from pulsed electron paramagnetic resonance spectroscopy 01.10.2019 Project funding (Div. I-III)
192650 Exploring the molecular basis of disease heterogeneity in TDP-43 proteinopathies 01.03.2021 Project funding (Div. I-III)
173333 Probing the interaction mechanisms of intrinsically disordered proteins with single-molecule spectroscopy 01.04.2017 Project funding (Div. I-III)
141735 NCCR RNA & disease: Understanding the role of RNA biology in disease mechanisms (phase I) 01.05.2014 National Centres of Competence in Research (NCCRs)

Abstract

A surprisingly large fraction of proteins contain extended regions or domains that lack a stable three-dimensional structure under physiological conditions. It is becoming increasingly clear that these intrinsically disordered regions (IDRs) play important roles in many cellular functions and are correspondingly often involved in pathological processes. A particularly important and large group of molecules with high abundance of IDRs are proteins involved in RNA binding and processing. However, the functional relevance of these conserved regions and their impact on disease development are largely unclear, to a large part because of the experimental challenges in investigating systems with such large conformational heterogeneity and pronounced dynamics. In this collaborative project, we combine the expertise of four prominent research groups with highly complementary expertise, both conceptually and methodologically, to address this elusive issue. We bring together the most important methods for the investigation of proteins containing large unstructured regions and their interactions and functional properties, both in vitro and in vivo: nuclear magnetic resonance spectroscopy (NMR), single-molecule Förster resonance energy transfer (FRET), electron paramagnetic resonance spectroscopy (EPR), biochemistry methods, human cells, organotypic slice cultures, and fluorescence microscopy. Conceptually, our groups integrate leading expertise in the function and conformational properties of RNA, RNA-binding proteins, conformationally heterogeneous systems, and the role of RNA-binding proteins in the molecular pathogenesis of neurodegeneration.In this unique combination, we will •establish the methodology for obtaining a complete picture of the structural ensembles of RNA-binding proteins containing disordered regions,•elucidate the effect of intrinsically disordered regions on protein-RNA and protein-protein interactions and their functional consequences,•identify the role and structural properties of IDRs for protein-RNA interactions involved in liquid-liquid phase separation and stress granule formation,•characterize how the transition from liquid-like droplets to pathogenic inclusions is controlled by protein-RNA interactions and intrinsically disordered regions.
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