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Charting the Structure, Function and Modulation of Splicing Factors' Intrinsically Disordered Regions to Unlock mRNA Processing Regulation
Aim of the project
Aim of the project
In this project we propose to fill the gap of knowledge on the structure and function of the spliceosome's (SPL) intrinsically disordered regions (IDRs), focusing on SF3B1. To this end we will synergically use NMR, SAXS and Molecular Dynamics simulations taking advantage of the complementary expertise of the research units involved in this project. Besides advancing a fundamental understanding of the splicing mechanism, our study will set the basis to expand the druggable SPL proteome towards its IDP/IDRs. This will aid in developing innovative therapeutic strategies to fight human diseases associated with splicing deregulation.
Task 1
Task 1
Computational Modelling and ensemble generation of NTD-SF3B1 in the SF3b complex using AI driven tools (Alphafold, Colabfold etc.)
Task 2
Task 2
All-atom and coarse grained (classical /enhanced sampling) molecular dynamics simulation of the selected frames from the AI driven ensemble.
Task 3
Task 3
Expression of NTD-SF3B1 (wild type and phosphorylated) and purification for CD, NMR, SAXS, HDX-MS etc measurements.
Task 4
Task 4
Validation of the molecular dynamics simulations using experimental parameters.
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