Ricerc@Sapienza

The concept that a substantial fraction of the encoded proteins are intrinsically disordered (IDPs) or contain intrinsically disordered regions (IDRs), that are nevertheless fully functional, has revolutionized our understanding of protein science. This finding has directly challenged the classic view implying 'sequence determines structure determines function'. Since their discovery, IDPs and IDRs have been implicated in several cellular functions, being recognized and/or post-translationally modified by structured domains of interacting partners. Importantly, a number of pathologies have been linked to IDPs, demanding for a better understanding of the physical-chemical principles underlining their function.
Among IDPs, a particularly interesting role is played by Short Linear Motifs (SLiMs), consisting of short stretches of typically 3 to 12 amino acids that, despite their small size, mediate crucial interaction between protein partners often acting as regulators of entire pathways. SLiMs function has been associated with disease. For instance, both papilloma virus and SARS-CoV-2 hijack endogenous SLiMs to cause cervical cancer and facilitate lung infection, respectively.
Another example of recognition afforded by the presence of an IDR is provided by nucleophosmin (NPM1). This protein is overexpressed and mutated in a number of cancers and used by several viruses, including HIV and HBV, to transport viral proteins to nucleoli. Mutations at the IDR compromise this function and have been described in solid cancers and dyskeratosis congenita.
This project is designed to investigate the interactions of selected SLiMs with SH2, SH3 and PDZ domains from protein partners and how these interactions are deranged in cancer and viral infections. Moreover, the role of NPM1 IDR in mediating interactions with fibrillarin and snoRNAs will be investigated. Finally, our structural studies will be used to search for small lead compounds that interfere with these interactions.