Mattia D’Agostino

The initiation factor 5A (IF5A) is one of the universally conserved traslation factors. There are homologs in Eukarya (eIF5A) and in Archea (aIF5A) and an orthologue in Prokaryotes (EF-P). eIF5A has been improperly included among the initiation factors, in fact, IF5A recognizes ribosomes that are stalled during the elongation phase of the traslation process. This protein is essential for cell viability and it is the only protein known that contains the amino acid residue hypusine, formed, in Eukarya, by post-translational modification of a specific lysine residue by two enzymes: Deoxy-hypusine sinthase (DHS) that converts lysine in deoxyhypusine, and Deoxy-hypusine hydroxylase (DOHH) that trasforms the deoxyhypusine residue to hypusine. As most translation factors, which are essential in protein synthesis and therefore in cell growth and proliferation, even high and unusual IF5A expression levels have been related to different tumor types. Given the unique post-translational modification, eIF5A could represent a specific target for the treatment of neoplastic forms. In this case several DHS inhibitors have been tested in the treatment of many types of cancer, one of this is the spermidine analog GC7. One part of my phD project focus on the structural characterization of the complex between the IF5A and the DHS, firstly through the purification of the recombinant proteins then with methods aimed to resolve the structural resolution of the complex between the two proteins: x-ray crystallography and cryo-electron microscopy, with the final goal to study potential inhibitors of the IF5A-DHS interaction through bioinformatic techniques like docking and molecular dynamics.