INFORMAZIONI SU
MURACA Valentina
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Supervisori: Prof.ssa Corazza e Prof.ssa Lippe
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| Mitochondrial ATP synthase is the core of energy conservation in mammalian cells. It consists of a catalytic F1 and intramembrane FO subcomplexes connected by a central stalk (CS) and a peripheral stalk (PS). Besides ATP production and cristae formation, ATP synthase is involved in generating the permeability transition pore (PTP), a channel mediating fast Ca2+ release (associated to short open times) and cell death (consequent to long-lasting opening). Therefore, it is worth investigating the mechanisms underlying the transition of ATP synthase to the PTP, because of its role in several diseases too. The PTP opening is triggered by the interaction of the matrix protein Cyclophilin D (CyPD), which is endowed of peptidyl prolyl cis/trans isomerase activity, with the oligomycin-sensitivity conferral protein (OSCP), an ATP-synthase subunit. Recent work revealed that CypD can undergo post-translational modifications, including cysteine residues oxidation and phosphorylation of serine residues mediated by the protein kinase GSK3β that increase the PTP opening probability. The laboratory where I started my PhD project has recently characterized the secondary structure and the residue-by-residue mobility of the human CyPD by Nuclear Magnetic Resonance (NMR), demonstrating that the N-terminal tail is highly flexible, in sharp contrast with the remaining globular rigid part of the protein. Moreover, in vitro experiments revealed that this portion plays a regulatory role on the CyPD-ATP synthase interaction, which is critical for PTP opening. A first task of my PhD project is to evaluate the influence of the CyPD N-terminus on the CyPD susceptibility to oxidative stress and to GSK3β-mediated phosphorylation (potentially promoting PTP). A second task is to probe the susceptibility of the CyPD N-terminus to proteolytic cleavage. |
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