Prions and molecular chaperones.

Abstract

Molecular chaperones are proteins involved in the folding of other proteins. Among these chaperones, some are involved in their own folding (auto-chaperones). A question arises: what is the mechanism of the chaperone folding catalysis? A model for protein folding that uses the thermodynamics of irreversible processes and statistical mechanics to describe the phenomenon is proposed; the analysis presents a clear link between these two aspects. A consequence of this model is the possible existence of misfolded proteins. This point is discussed and some experimental results arguing in this direction detailed. This thermo-kinetic model is applied to protein folding driven by a molecular chaperone. Analysis of folding shows that a misfolded chaperone can induce misfolding in protein and, in the case of autofolding (auto-chaperone), may lead to new misfolded chaperones. The consequences are explored by computer simulations. They show that such an auto-chaperone could behave as a new kind of informative molecule and replicate a misfolded structure by a process similar to infection. A quantitative model, displaying the epidemiologic characters of prion infections, is derived from this hypothesis. This hypothesis satisfactorily explains the three manifestations (infectious, genetic and sporadic) that are the characteristic features of all prion diseases. Are prions really molecular chaperones required for their own assembly? Analysis of the structure of prions revealed some features shared by true molecular chaperones. This analysis suggests the positions of the mutations likely to lead to the characteristic early onset of encephalopathy. They are in good agreement with experimental results.