Project description:The existence of interactions between many cellular proteins and various polyanionic surfaces within a cell is now well-established. The functional role of such interactions, however, remains to be clearly defined. The existence of protein arrays, with a large selection of different kinds of proteins, provides a way to better address a number of aspects of this question. We have therefore investigated the interaction between five cellular polyanions (actin, tubulin, heparin, heparan sulfate (HS), and DNA) and approximately 5,000 human proteins using protein microarrays in an attempt to better understand the functional nature of such interaction(s). We demonstrate that a large number of polyanion binding proteins exist which contain multiply positively-charged regions, are often disordered, are involved in phosphorylation processes, and appear to play a role in protein-protein interaction networks. Considering the crowded nature of cellular interiors, we propose that polyanion binding proteins (PABPs) interact with a wide variety of polyanionic surfaces in cells in a functionally significant manner. Keywords: Protein-Protein, protein-polyanion Interaction
Project description:Targeted protein degradation is a cutting-edge approach in drug discovery, especially for addressing disease-related proteins that have been difficult to target with traditional methods. Here, we present a conceptually distinct strategy utilizing G-quadruplex (G4) ligand-based PROTACs (G4L-PROTACs) to selectively degrade proteins associated with DNA and RNA G-quadruplexes. Our method leverages G4 ligands that bind endogenous G4s and recruit E3 ubiquitin ligases to promote the degradation of cellular G4-binding proteins. We demonstrate degradation of a range of G4-specific binding proteins, including transcription factors and chromatin remodelers such as FUS, SMARCA4, and ATRX. These proteins play crucial roles in diverse cellular processes like transcription regulation and DNA repair, making them important therapeutic targets. Our results highlight the potential of G4L-PROTACs as a versatile tool for selectively degrading G4-binding proteins, offering new possibilities for therapeutic protein degraders, especially in diseases characterized by aberrant G4 activity, such as cancer.