Strategies toward understanding intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) lack a persistent defined structure in the absence of biomolecular interactions. In the early days of the protein structure-function paradigm, solving the structure was the “holy grail” toward understanding its function. We now know that other important factors also play a role. IDPs were thought to be unstructured polypeptide regions of little consequence to protein structure and function. However, their importance and richness of diverse functions in biology has begun to emerge. Like structured proteins, their dynamics and interactions are critical to understanding their function in a biological context. Yet this remains a major challenge in their study. Little information is available to predict their behavior ab initio. Structure prediction programs have facilitated these efforts, especially in predicting disordered regions in proteins. The challenge in experimentally determining the behavior of IDP/Rs is there are few techniques suited to capture their dynamic behavior. Biophysical approaches to study IDP/Rs along with their role in biological function is discussed along with three case studies. The human adenosine A2A receptor, a G-protein coupled receptor, has a long C-terminal disordered tail. Reports suggest it plays a role in homo-dimerization. Others suggest it is involved in recruiting other biomolecules and receptor desensitization. Caveolin, which has three major isoforms, contains a disordered N-terminal region believed to be involved in various interactions including regulating homo-interactions of the protein. Lastly, the role of IDP/Rs in irreversible aggregation, which leads to dementia-related diseases, is discussed. Important questions surrounding these IDP/Rs are highlighted and biophysical strategies to address these questions are described. The goal is to begin developing a roadmap to enable researchers to elucidate IDP behavior and understand their function as part of the greater intracellular ensemble.