Unpicking the Specificity of the Protein Quality Control Network in Health and Disease

Inside human cells, a protein called DNAJB6b acts like a quality-control inspector that can either help refold damaged proteins or stop them from clumping into toxic aggregates—but no one knows exactly how it decides which job to do. This matters because when the cell’s protein quality-control system fails, proteins misfold and clump together, driving diseases like neurodegeneration and certain muscle disorders. The Hsp70 chaperone machine is the main tool cells use to fix misfolded proteins, but it relies on helper proteins called Hsp40s (DNAJs) to direct it to the right targets. DNAJB6b is one such helper, and mutations in it are linked to disease. Yet the molecular mechanisms that let it recognise specific toxic clients and either refold them or block their aggregation remain unknown. This project will use a combination of NMR spectroscopy, mass spectrometry, cryo-electron microscopy, cell-based assays, and organismal models to reveal how DNAJB6b’s long, low-complexity regions control its interactions with Hsp70 and its own ability to self-assemble and inhibit aggregation. The research is fundamental science—it aims to understand a core cellular process rather than produce an immediate therapy. But by revealing the molecular origins of DNAJB6b’s specificity, it could open the way to engineering optimised chaperones or small-molecule drugs tuned to target different disease-related protein aggregates.