Project Details
Projekt
Theory for phase separation and aggregation regulated by chaperones
Applicant
Professor Dr. Christoph Weber
Subject Area
Biophysics
Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200
Many aggregation-prone proteins can phase separate in living cells and reconstituted in-vitro systems. Specialized proteins that are part of the protein quality control machinery, called chaperones, were shown to inhibit protein aggregation or precursor molecular transitions, such as misfolding. Interestingly, such chaperones act as complexes and exhibit two interaction modes with proteins: chaperones passively bind (holdase) or hydrolyze ATP for binding and release (foldase). Recently, using theory, we showed that the coupling between phase separation and aggregation of macromolecules gives rise to unusual size distributions of aggregates in each phase and a transition to a gel phase with solid-like properties. However, a theoretical framework is lacking that describes how chaperones and chaperone complexes interfere with protein aggregation when proteins are phase-separated. The non-dilute conditions, the effects of ATP hydrolysis of chaperones, and the heterogeneous environments (concentration gradients, interfacial effects) define a challenging and highly relevant theoretical problem at the intersection with biology. This proposal fills this gap by developing theoretical approaches on how chaperone potency and efficacy are intertwined with protein phase separation and aggregation. These theoretical approaches will be derived and applied in close collaboration with experimental groups within the FOR consortium. Quantitative comparisons of concentration fields in space and time to experimental data obtained from measurements using Fluorescence Resonance Energy Transfer (FRET) and confocal imaging will allow us to quantify the kinetic and thermodynamic parameters of the experimental systems and thereby pave the way to unravel the molecular mechanisms of how chaperones regulate aggregation phase-separated systems.
DFG Programme
Research Units
