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NMR structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation

English title NMR structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation
Applicant Allain Frédéric
Number 170130
Funding scheme Project funding (Div. I-III)
Research institution Institut für Molekularbiologie und Biophysik ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Molecular Biology
Start/End 01.10.2016 - 30.09.2019
Approved amount 834'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biophysics

Keywords (10)

protein-RNA recognition; IRES; translation regulation; Mass spectrometry; Hybrid approaches; splicing regulation; RNP; NMR structure; U1snRNP; mRNA splicing

Lay Summary (French)

Lead
Structure RMN de complexes ARN-proteines impliqués dans l'epissage alternatif et la régulation de la traduction.
Lay summary

Comprendre les mécanismes de la regulation post-transcriptionelles est très important pour la santé humaine car ils sont a l'origine de nombreuses maladies génétiques. Les protéines qui se lient a l'ARN sont des facteurs essentiels du controle de cette régulation.

Nous proposons ici de déterminer la structure tridimentionelle de plusieurs facteurs protéiques en liaison avec l'ARN (PTB, Unr, DND1, hnRNPA1 et hnRNP C). La connaissance précise de ces structures permettra non seulement de comprendre leur mode d'action mais aussi de pouvoir élaborer de nouvelles voies thérapeutiques contre certaines maladies génétiques.

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Direct link to Lay Summary Last update: 23.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Structural basis of a small molecule targeting RNA for a specific splicing correction
Campagne Sébastien, Boigner Sarah, Rüdisser Simon, Moursy Ahmed, Gillioz Laurent, Knörlein Anna, Hall Jonathan, Ratni Hasane, Cléry Antoine, Allain Frédéric H.-T. (2019), Structural basis of a small molecule targeting RNA for a specific splicing correction, in Nature Chemical Biology, 15(12), 1191-1198.
Combining Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) Spectroscopy for Integrative Structural Biology of Protein–RNA Complexes
Leitner Alexander, Dorn Georg, Allain Frédéric H.-T. (2019), Combining Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) Spectroscopy for Integrative Structural Biology of Protein–RNA Complexes, in Cold Spring Harbor Perspectives in Biology, 11(7), a032359-a032359.
SAM68 interaction with U1A modulates U1 snRNP recruitment and regulates mTor pre-mRNA splicing
Subramania Suryasree, Gagné Laurence M, Campagne Sébastien, Fort Victoire, O’Sullivan Julia, Mocaer Karel, Feldmüller Miki, Masson Jean-Yves, Allain Frédéric H T, Hussein Samer M, Huot Marc-Étienne (2019), SAM68 interaction with U1A modulates U1 snRNP recruitment and regulates mTor pre-mRNA splicing, in Nucleic Acids Research, 47(8), 4181-4197.
Combining NMR Spectroscopy and Molecular Dynamic Simulations to Solve and Analyze the Structure of Protein–RNA Complexes
Campagne Sebastien, Krepl Miroslav, Sponer Jiri, Allain Frederic H-T. (2019), Combining NMR Spectroscopy and Molecular Dynamic Simulations to Solve and Analyze the Structure of Protein–RNA Complexes, Elsevier, New-york, 393-422.
Bacterial Regulatory RNA
Michel Erich, Duss Olivier, Allain Frédéric H.-T. (2018), Bacterial Regulatory RNA, Springer New York, New York, NY.
Orthogonal Tyrosine and Cysteine Site-Directed Spin Labeling for Dipolar Pulse EPR Spectroscopy on Proteins
Gmeiner Christoph, Klose Daniel, Mileo Elisabetta, Belle Valérie, Marque Sylvain R. A., Dorn Georg, Allain Frédéric H. T., Guigliarelli Bruno, Jeschke Gunnar, Yulikov Maxim (2017), Orthogonal Tyrosine and Cysteine Site-Directed Spin Labeling for Dipolar Pulse EPR Spectroscopy on Proteins, in The Journal of Physical Chemistry Letters, 8(19), 4852-4857.
Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7
Beusch Irene, Barraud Pierre, Moursy Ahmed, Cléry Antoine, Allain Frédéric Hai-Trieu (2017), Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7, in eLife, 6, 1-35.
Structural modeling of protein–RNA complexes using crosslinking of segmentally isotope-labeled RNA and MS/MS
Dorn Georg, Leitner Alexander, Boudet Julien, Campagne Sébastien, von Schroetter Christine, Moursy Ahmed, Aebersold Ruedi, Allain Frédéric H-T (2017), Structural modeling of protein–RNA complexes using crosslinking of segmentally isotope-labeled RNA and MS/MS, in Nature Methods, 14(5), 487-490.
Spin labelling for integrative structure modelling: a case study of the polypyrimidine-tract binding protein 1 domains in complexes with short RNAs
Gmeiner Christoph, Dorn Georg, Allain Frédéric H. T., Jeschke Gunnar, Yulikov Maxim (2017), Spin labelling for integrative structure modelling: a case study of the polypyrimidine-tract binding protein 1 domains in complexes with short RNAs, in Phys. Chem. Chem. Phys., 19(41), 28360-28380.

Collaboration

Group / person Country
Types of collaboration
Adrian Krainer/CSHL United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Gunnar Jeschke/ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Ruedi Aebersold/ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
keystone meeting on RNP Talk given at a conference u1snRNP interaction with small molecule and proteins 24.03.2019 whistler, Canada Allain Frédéric;
meeting on drug discovery Talk given at a conference Small molecule-RNA interaction 20.03.2019 cannes, France Allain Frédéric;
louis jeantet symposium Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 09.10.2018 geneva, Switzerland Allain Frédéric;
ICMRBS Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 20.08.2018 dublin, Ireland Allain Frédéric;
seminar Individual talk hybrid approaches to solve the structures of large protein-RNA complexes 19.06.2018 regensburg, Germany Allain Frédéric;
translation research in Zurich Talk given at a conference structural basis of small molecule-RNA interaction 22.01.2018 zurich, Switzerland Allain Frédéric;
Riboclub Talk given at a conference Solution structure of FUS bound to RNA 25.09.2017 montreal, Canada Allain Frédéric;
symposium on RNA and RNP structure Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 23.09.2017 heifei, China Allain Frédéric;
computational aspect of protein-RNA interaction Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 19.06.2017 Dagstuhl, Germany Allain Frédéric;
RNA society meeting Talk given at a conference combining NMR and MS to determine the structure of RNP 30.05.2017 prague, Czech Republic Dorn Georg;
keystone meeting in NMR spectroscopy Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 13.03.2017 keystone, United States of America Allain Frédéric;
isotope labelling in NMR spectroscopy Talk given at a conference hybrid approaches to solve the structures of large protein-RNA complexes 06.03.2017 grenoble, France Allain Frédéric;


Associated projects

Number Title Start Funding scheme
189379 Structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation 01.10.2019 Project funding (Div. I-III)
149921 NMR structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation 01.10.2013 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

Understanding the molecular mechanisms regulating gene expression is a major question in molecular biology, defects in these mechanisms being at the origin of many genetic diseases and cancers. This proposal focuses on two of these processes: splicing regulation and translation regulation. Gene regulation plays a major role in many diverse cellular processes such as embryonic development, cell differentiation and synapse activation. We focus here on aspects of gene regulation that are under the control of RNA binding proteins (RBP). Regarding splicing regulation, we are focusing our attention to how the U1snRNP interact with various alternative-splicing factors like SR proteins or hnRNP proteins or how hnRNP A1 multimerize to repress splicing. Regarding translation regulation our main efforts are with three RBPs, PTB, dnd1 and the bacterial protein RsmE. Finally, more generally, we would aim at fully understanding the RRM-RNA code of recognition and also how motions can influence RNA binding recognition with examples of allosteric anti-cooperativity. To achieve these aims, we will combine experimental and computational approaches to achieve this goal.We will use hybrid approaches that combine NMR with EPR, SAXS and possibly EM. Furthermore we will use mass-spectrometry in combination with NMR to model low resolution protein-RNA complexes. We will develop a rapid approach allowing us to study several dozens of RRM-RNA complexes.
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