Grant: Project Grant

The biological function and disease-causing malfunction of proteins are underpinned by their structures and interactions with themselves and other biomolecules. Despite tremendous progress in past decades, the basic driving forces of protein conformational changes are not well understood, limiting the application of biophysical knowledge of disease-related proteins in therapeutics development. The need for a deeper physical understanding is especially acute for intrinsically disordered proteins (IDPs) that lack a stable structure. Comprising ~30% of the proteome, IDPs are prominently involved in cellular regulation, a role facilitated by IDPs' ability to perform dynamic, multi-site recognition of other biomolecules. Malfunctioning of IDPs causes numerous diseases, notably various forms of cancer and neurological degeneration. A remarkable recent discovery is that liquid-liquid phase-separated IDPs -- like oil droplets in water -- are a major component of functional compartments in the cell. However, the biophysical basis of individual and collective IDP properties remains mostly undeciphered. The proposed research builds on the fundamental advances we have recently made, particularly in understanding how IDP phase separation depends on their amino acid sequences. Harnessing the unique interdisciplinary expertise of our own research group as well as those of our collaborators, we endeavour to expand significantly our fundamental physico-chemical knowledge of biomolecular organization and recognition for the novel multi-site interactions and liquid-liquid phase behaviours of IDPs. Results of our investigation will enable advances in understanding disease processes and ultimately to developing new therapies.