Higher eukaryotic proteomes contain extensive unstructured intrinsically disordered regions. These regions often control the localisation, stability and modification state of a protein. Yet, the functional role of the vast majority of these regions is still unknown. Various estimates have suggested that there may be upwards of one hundred thousand interaction interfaces in these regions. However, to date, only a small portion of the functional elements predicted to reside within these regions have been characterised. The majority of known interfaces in disordered regions belong to a class of compact, degenerate and ex nihilo evolvable interaction modules known as short, linear motifs (SLiMs). In this talk, we introduce our recent work characterising the regulatory SLiM modules recognised by the two key enzymes, the Anaphase-Promoting Complex/Cyclosome (APC/C) and Protein Phosphatase 2A (PP2A). We discuss how the information encoded in the sequence of the disordered regions allow these proteins to alter their function in reaction to cell state changes, thereby allowing conditional decision-making. Finally, the growing consensus that the disordered regions of proteins are the key determinant of the post-translation regulation that controls the life of almost all proteins from their synthesis to their destruction will be discussed.
Speaker Biography: Norman received his Ph.D. degree (2009) from the Conway Institute of Biomolecular & Biomedical Research at University College Dublin, Dublin, Ireland, working on short, linear motif discovery methods. He subsequently moved to the European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, as an EIPOD postdoctoral fellow to work on various aspects of motif biology including the prominent role of SLiMs in regulatory decision-making, splice isoform-specific functionality, and viral pathogenesis. In 2013, he joined the Department of Physiology at the University of California, San Francisco (UCSF) as a postdoctoral fellow with Professor David O. Morgan characterizing novel motifs in the cell cycle. In September 2014, he returned to University College Dublin to start his own group studying motif function. In 2017, he was a Visiting Professor at the Dana-Farber Cancer Institute at Harvard Medical School working on the molecular details of immunosuppression. His research focuses on the role of SLiM within intrinsically disordered regions in directing cell regulation. He has authored over 40 papers on various aspects of SLiM biology. He continues to utilize evolutionary, proteomic, and genomic data to examine two major open questions about intrinsically disordered regions: (i) what are the modules that are responsible for their functionality and (ii) how do perturbations in the cell modulate the functionality of these modules.