Project description
Time-lapsed ‘still shots’ of the spliceosome in action
Gene expression relies on pre-messenger RNA (pre-mRNA) production from nuclear DNA followed by removal of the introns, non-coding regions, and covalent bonding of the extrons, the coding portions, to produce mature mRNA. The latter is the template for protein production in the cytoplasm. The spliceosome is a large RNA-protein complex that catalyses intron removal. Building on its recent determination of the crystal structure of three of five subunits of the spliceosome, the European Research Council-funded SPLICE3D project will determine the structure of the entire spliceosome at different steps of splicing. Putting together these ‘still shots’ will reveal the molecular mechanisms of pre-mRNA splicing and insight into gene expression in health and disease.
Objective
The protein coding sequences of the majority of eukaryotic genes are interrupted by non-coding introns. The spliceosome is an immense and intricate molecular machine that catalyses the excision of introns from pre-mRNAs and splicing together of exons to produce mature mRNA. This is a crucial process in eukaryotic gene expression and we aims to greatly increase our understanding of its molecular mechanism through cryoEM studies of the spliceosome. The spliceosome comprises five canonical subunits, namely U1, U2, U4, U5 and U6 small nuclear ribonucleoprotein particles (snRNPs) and numerous non-snRNP factors. During the initial stages, U1 and U2 snRNPs bind the 5’-splice site and branch point of pre-mRNA, respectively, and the spliceosome is fully assembled when the U4/U6.U5 tri-snRNP is recruited. The spliceosome then becomes activated through extensive structural and compositional remodeling which leads to the formation of the catalytic RNA core. Recently we determined the crystal structure of U1 snRNP and two key spliceosomal proteins: Prp8, which harbours the catalytic RNA core and Brr2, which catalyses the rearrangement of the RNA interaction network and plays a crucial role in spliceosomal activation. We also solved the structure of U4/U6.U5 tri-snRNP by cryoEM and revealed the nearly complete organisation of U5 snRNA and U4/U6 snRNA and over 30 proteins within this complex, providing crucial insights into the activation mechanism and the active site of the spliceosome. Building on these achievements we aim to determine the structure of the entire spliceosome stalled at different steps of the splicing reaction so that the molecular mechanism of pre-mRNA splicing is understood in structural terms. This will enormously increase our understanding of this fundamental process of eukaryotic gene expression and such knowledge will clarify the molecular pathology of diseases caused by mutations in spliceosomal components and may facilitate therapeutic intervention.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences physical sciences optics microscopy electron microscopy
- natural sciences biological sciences genetics nucleotides
- natural sciences biological sciences genetics RNA
- natural sciences biological sciences molecular biology
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
-
H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
See all projects funded under this programme
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-ADG - Advanced Grant
See all projects funded under this funding scheme
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2015-AdG
See all projects funded under this callHost institution
Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
SN2 1FL SWINDON
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.