A bacterial protein called SAP05 acts as a molecular glue, directly sticking unwanted proteins to the cell’s recycling machinery and destroying them without needing the usual tagging system. This matters because current methods for targeted protein degradation—such as PROTACs—require a two-step process where a protein is first tagged with a small molecule called ubiquitin before being fed to the proteasome. SAP05 bypasses that step entirely, offering a simpler, potentially faster way to knock down specific proteins inside cells. The project will combine biophysics, biochemistry, and genetics to understand exactly how SAP05 selects its targets and to engineer synthetic versions that can be programmed to degrade different proteins on demand. If successful, the SAP-ERASER technology could become a versatile research tool for turning off proteins in organisms ranging from yeast and plants to humans. It would complement existing gene-editing tools like CRISPR, but at the protein level—useful for studying diseases, validating drug targets, or developing new therapeutics. The work is fundamental science: it asks how a bacterial protein hijacks a cell’s disposal system, and that knowledge may open unexpected applications in biotechnology and medicine.
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SAP-ERASER is an ambitious high-risk/high-gain program to deliver a radically novel Targeted Protein Degradation (TPD) technology. SAP effectors are secreted bacterial proteins that mediate the degradation of host transcription factors using different mechanisms. SAP05 effectors directly bind a 26S proteasome component leading to the degradation of protein substrates independently of E3 ligases and ubiquitination. SAP05 mode of action is unique because other proteolysis-targeting systems, such as PROTAC, depend on substrate ubiquitination and E3 ligases for proteasome-dependent degradation. SAP05 acts as a molecular glue that sandwiches a substrate and the 26S proteasome receptor RPN10 leading to efficient degradation of the substrate. Thus SAP05 offers the opportunity for a unique protein knock-down technology with many applications in biotechnology and biomedicine that complement existing gene knock-down tools, such as CRISPR-Cas and RNA interference. Here, I will combine biophysical, biochemical and genetic approaches to determine how SAP05 effectors selectively recruit proteins for degradation and to develop synthetic SAP05 variants with novel substrate binding specificities. I designed the project around three interconnected and complementary Work Packages (WPs), which are biophysics, substrate binding specificity and protein degradation technology. The gained knowledge will serve as a framework to develop the SAP-ERASER technology as an impactful targeted protein degradation tool for research, therapeutic and biotechnological applications in a variety of organisms, including humans, animals, yeast and plants.
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