Self-assembling multi-functional biomolecular condensates for targeted degradation of disease-associated proteins
We are developing artificial multi-valent proteins capable of liquid-liquid phase separation (LLPS) with the aim of building multi-functional biomolecular condensates and thereby harnessing specific cellular enzymes to target disease-associated proteins for destruction. We propose to design condensates that contain a class of proteins known as tandem-repeat proteins (RPs). We have shown that RPs are strikingly amenable to rational design and can be engineered to simultaneously bind multiple proteins, bringing them into specific spatial proximity in such a way as to enable a chemical modification of the target protein. The rational design of LLPS systems capable of selectively recruiting client proteins into them to drive specific biological reactions would enable both a deeper understanding of the role of biomolecular condensates in nature as well as the exploitation of their remarkable physico-chemical properties for therapeutic effect.
Key areas of interest include:
- Understanding the molecular grammar of protein phase separation to define rules for creating designer LLPS systems.
- Developing novel hetero-bifunctional phase-separating proteins to recruit disease-associated targets to the protein degradation machinery.
- Translating the designed LLPS proteins into biomolecular condensates in the cell capable of enhancing targeted protein degradation.