Alternative RNA splicing is an essential process leading to multiple protein isoforms from a single gene. Our understanding of its regulation is very poor. Strikingly, portions of the pre-mRNA can be bound by numerous proteins, activators and repressors, that have effects on the splicing outcome, but they cannot all fit on at once. Do proteins bind independently and transiently, the outcome being a matter of chance, do they bind stably in defined combinations, where several combinations might permit splicing and others block it, or do activators and repressors bind competitively at a single crucial site? To answer these questions, we will combine Nuclear Magnetic Resonance (NMR) in nuclear extracts, X-ray crystallography, Small Angle X-ray Scattering (SAXS), Isothermal Titration Calorimetry (ITC), and fluorescence anisotropy to investigate structurally and biophysically protein pairs that are known to cooperate (Sam68/hnRNP A1) or compete (hnRNP A1/SRSF1) for splicing of the SMN2 pre-mRNA.
Academic entry requirements: UK Bachelor Degree with at least 2:1 in a relevant subject or overseas equivalent.