Protein folding, misfolding and protein disease

Project description

Our projects are directed along the following lines:
- Studies of the folding nucleus and the folding energy landscape and how these respond to changes in topology (natural and tailor made) and amino-acid composition. A central objective is to identify the features of the folding reaction that are controlled by biology (i.e. evolved features) and those that are limited by the folding physics.
- Studies of conformational gatekeepers – the role of some conserved residues is not primarily to form native contacts but to control misfolding and aggregation through negative design.
- Folding in confined space. In the cell, folding often occurs in confined space but there are hardly any data on how conformational restrictions affect protein stability and folding cooperativity.
- Studies of pathogenic fibrillation processes with specific focus on the role of sequence “stickiness”, protein stability and native-state plasticity. The project is also aimed at design of protein and peptide constructs with well defined aggregation pathways for in vivo studies.
- Common denominators of Cu/Zn SOD mutations associated with ALS. Recent indications of a folding related cause of ALS as well as new methods to rationally produce SOD mutants have open the door to a large-scale effort on the ALS mechanism.