Proteins are key players in virtually all biological events and accomplish their function as part of larger protein complexes. Unfortunately, compared to the structure determination of individual proteins, structural characterization of protein-protein interactions is much more complex and is a significant challenge in structural biology. For transient interactions, it is even more difficult since the interactions only last for a short period; they are hard even to detect and thus even harder to study in molecular detail. Yet these transient interactions are vital for regulating complex signaling networks that determine typical cell fate or lead to diseases such as cancer, autoimmunity, and cardiovascular and neurological disorders. In this proposal, we suggest an integrative approach combining new technologies in proteomics with structural bioinformatics and computational modeling to study and understand highly dynamic transient interactions. We will develop computational tools to study protein-protein interactions involving disorder and tools that can be used to turn binary interaction maps into 3D models for further investigation and characterization.
In the applied part of the project, we aim to analyze the interaction networks of four IDPs and their role in human health and disease: the oncoprotein MYC, the recently identified DIORA1 in autoimmune disease, TP53BP1 in breast cancer, and Apollo in DNA repair.
In addition, we will also use the current allocation to continue developing our improved version of AlphaFold, which was deemed best in the community-wide benchmark CASP15.