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

English title Structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation
Applicant Allain Frédéric
Number 189379
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 Biochemistry
Start/End 01.10.2019 - 30.09.2022
Approved amount 834'000.00
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All Disciplines (2)

Discipline
Biochemistry
Biophysics

Keywords (8)

CryoEM; hybrid approaches; RNP; hnRNP; translation regulation; NMR structure; Protein-RNA recognition; splicing regulation

Lay Summary (French)

Lead
Frederic Allain
Lay summary

Structure RMN de complexes ARN-protéines impliqués dans l'épissage alternatif et la régulation de la traduction.

 

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

Nous proposons ici de déterminer la structure tridimensionnelle de plusieurs facteurs protéiques en liaison avec l'ARN (PTB, SRSF1, 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.

Direct link to Lay Summary Last update: 16.10.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
170130 NMR structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation 01.10.2016 Project funding (Div. I-III)
141898 NMR studies of GPCRs: Structure, dynamics and interactions with ligands and signaling proteins 01.12.2012 Sinergia
182880 NCCR RNA & disease: The role of RNA biology in disease mechanisms (phase II) 01.05.2018 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 (RBPs). Regarding splicing regulation, we are investigating on how the U1snRNP interacts with various alternative-splicing factors like SR proteins or hnRNP proteins to modulate the splicing outcome or how hnRNP A1 and hnRNP C multimerizes in order to form a ribonucleoparticle. Regarding translation regulation our main efforts are the bacterial protein RsmE. Finally, more generally, we would aim at fully understanding how molecular motions can influence RNA binding recognition with two example of allosteric anti-cooperativity. To achieve these aims, we will combine experimental and computational approaches.We are proposing here to determine the 3D structures of several key RNP complexes involved in gene regulation, but also to understand how the dynamics of some RBP can influence RNA recognition. We will solve high resolution structures of several RBP bound to U1snRNP and of a large hnRNP particle possibly responsible to compact introns. We will also study the dynamics of hnRNP A1 and RsmE in order to better understand allosteric anti-cooperativity triggered by RNA recognition. Finally, based on these structures we will investigate the function of these RNA binding proteins using in vitro and in vivo assays that are already available in the lab.
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