Chaperone action - a thermodynamic view

Introduction

The goal of the proposed study is to obtain a fundamental understanding of the molecular mechanism and thermodynamics of chaperone action. Chaperones are critical components of all organisms and serve to ensure a healthy state of the proteome. The proposal concerns a class of chaperones that increases the solubility of client proteins.

Research Objectives

The activity of these chaperones exhibits a number of crucial but poorly understood features; for instance, there is a remarkable specificity in action combined with promiscuous recognition across sequence space. These features are challenging to achieve through molecular design and raise the question of the general physical principles which govern chaperone activity.

Our research aims to reach a general understanding, beyond specific effects, and we will study nine binary combinations of three chaperones and three client proteins.

Methodology

Our strategy is to first characterize in detail the aqueous solubility and self-assembly of each chaperone alone, including the phase behaviour. With this knowledge, and our existing deep understanding of client self-assembly, we turn to chaperone action to study:

1. The thermodynamics of chaperone-client mixtures
2. The phase behaviour
3. The structure of chaperone-client co-assemblies
4. The mixing stoichiometry
5. Quantitative equilibrium parameters

We use state-of-the-art scattering, spectroscopy, and microscopy methods and develop new methodology.

Novel Approach

Common to the field is a mechanical view and search for specific sites in chaperone and client proteins that mediate their mutual interaction, but the promiscuity makes us question whether such sites exist.

We take a new approach, not pursued by others in the field, in that we search for general molecular and thermodynamic principles of chaperone action.

Potential Impact

Our results may guide the design of small molecules that operate according to the same principles, which can serve as therapeutics toward some of the most devastating diseases affecting humans.