Kinetic analysis of R67 dihydrofolate reductase folding: from the unfolded monomer to the native tetramer.

R67 dihydrofolate reductase (DHFR) is a homotetrameric enzyme. Its subunit has a core structure consisting of five antiparallel beta-strands that form a compact beta-barrel. Our interest was to describe the molecular mechanism of the complete folding pathway of this beta-sheet protein, focusing on how the oligomerization steps are coordinated with the formation of secondary and tertiary structures all along the folding process.

Prion diseases: dynamics of the infection and properties of the bistable transition.

Prion diseases are thought to result from a pathogenic, conformational change in a cellular protein, the prion protein. The pathogenic isoform seems to convert the normal isoform in an autocatalytic process. In contrast to the conditions used for in vitro studies of enzyme kinetics, the concentration of the catalyst is not much lower than that of the substrate in the course of infection.

Multistability: a major means of differentiation and evolution in biological systems.

Very simple biochemical systems regulated at the level of gene expression or protein function are capable of complex dynamic behaviour. Among the various patterns of regulation associated with non-linear kinetics, multistability, which corresponds to a true switch between alternate steady states, allows a graded signal to be turned into a discontinuous evolution of the system along several possible distinct pathways, which can be either reversible or irreversible. Multistability plays a significant role in some of the basic processes of life.

Species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein.

Prion diseases are thought to result from the conformational change of the normal cellular prion protein to a pathogenic protease-resistant isoform. However, brain extracts not containing the protease-resistant isoform of the prion protein can be infectious following interspecies transmission. The 'protein-only' hypothesis of pathogenesis is extended to provide possible explanations which could be interpreted in terms of a different infectious agent.

Coordination of catalytic activities within enzyme complexes.

If two enzymes are physically and permanently associated as a bi-enzyme complex and if these enzymes catalyze non-consecutive chemical reactions, either of these reactions may inhibit or activate the other. If these reactions belong to two different metabolic cycles, the functioning of one of these cycles will control the fine tuning of the other. Thus simple kinetic considerations lead to the conclusion that, owing to the spatial organization of enzymes as multimolecular complexes, a fine tuning and a coordination of different metabolic networks, or cycles, may be exerted.