Hitting and neutralising intracellular protein interactions with a precision never before achieved. This is the objective of PISA (Post-translational Intracellular Antibodies Silencing), a technology developed by a team of students and researchers led by Professor Antonino Cattaneo, at the Laboratory Bio@SNS of the Scuola Normale Superiore. The technique has been described in an article published in Nature Methods, and will allow for the first time to interfere selectively and specifically with chemically modified intracellular proteins, at the last stage of their biosynthesis.
It is well known that each protein, after being synthesised starting from its corresponding gene, undergoes a series of numerous chemical modifications defined post-translational. This is why the collection of all the body’s proteins, called proteome, is so complex and still largely not understood.
For each gene there are many different proteins with post-translational modifications (let’s call them PTMs), often with different functions. PTMs mediate protein-protein interactions and are therefore necessary for the functioning of the network of cellular proteins. We can see PTMs as a “language”, a system of switches with which the intra-cellular proteins interact with each other to form a complex and dynamic network of proteins. In this intracellular “Internet network”, for example, a protein A with a certain PTM will “talk” to the protein B, while A and B cannot communicate in the absence of PTM, are “dumb” one for the other. This general mechanism has a huge physiological and, of course, pathological relevance.
It would be essential for the study of cell functions, and therefore to identify new attack strategies for the treatment of many diseases, to be able to interfere directly and selectively with the subset of a protein A with a given PTM, without affecting the original unchanged A protein. To date, with the techniques developed so far, this type of selective approach has not been possible, and none of the drugs approved by the FDA today can directly affect a PTM, despite the post translational proteome representing such a rich source of potential therapeutic targets.
The study published in Nature Methods shows how the PISA technology allows to selectively affect the post-translationally modified protein, ignoring its unmodified version. This will allow the study of the biochemical and cellular effects of selective PTM neutralisation, with an unprecedented resolving power.
Prof Cattaneo and colleagues are pursuing pharmaceutical and biotechnology industrial applications of the PISA technology in the field of neuro-degeneration, in a collaborative project involving all active Pisan institutions in the life sciences. The ultimate aim is the production of new molecules for diagnosis and treatment of disorders of the “heart-brain” axis.
The study, coordinated by Antonino Cattaneo in the Laboratory Bio@SNS, has seen the collaboration of graduate students Michele Chirichella (first author of the work) and Marco Fantini, fellows Martina Goracci, Simonetta Lisi and Mariantonietta Calvello and researcher Cristina Di Primio, together with researchers at the ‘Institute EBRI Levi-Montalcini.