Mechanisms driving and inhibiting solid phase transitions of proteins

Proteins are not isolated entities, but rather interact dynamically with each other and with molecular chaperones. This interplay is of particular significance for intrinsically disordered proteins (IDPs), which have been observed to form nanoclusters, biomolecular condensates, and – if unchecked – irreversible aggregates linked to neurodegeneration. Notwithstanding the clinical importance of these processes, the molecular rules that govern the transition from dynamic protein assemblies to hardened deposits remain poorly understood.

The primary focus of this group is the investigation of the regulatory mechanisms of protein assembly and aggregation by molecular chaperones, with a particular emphasis on small heat shock proteins (sHSPs). The group investigates how their unique binding modes and dynamic oligomerisation suppress the formation of toxic states and influence the material properties of condensates. In order to achieve this objective, advanced microfluidic and biophysical methods are developed and applied, in combination with quantitative fluorescence microscopy and other imaging approaches. These techniques enable the quantification of protein–chaperone interactions in complex mixtures, the resolution of heterogeneous clusters, and the tracking of structural transitions across multiple scales. The objective is to provide a mechanistic understanding of how chaperone systems safeguard the proteome by bridging molecular biophysics with disease biology, and to elucidate the underlying mechanisms by which such failure contributes to the onset of sporadic neurodegenerative disorders, with a view to inspiring novel therapeutic strategies.

Image: A schematic summary of the dilute and dense phases formed by many proteins. Phase separation produces dense droplets where aggregation, as shown for FUS, is promoted at the phase interface, while the dilute phase contains freely diffusing monomers, oligomers, fixed-size- or percolation-clusters. Images rendered using FUS (AF-P35637-F1) and FUS fibril (PDB: 7VQQ) structures.