LAUSR

Conserved families of molecular chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous, chaperone-independent folding; (ii) folding assisted by repetitive Hsp70 cycles; and (iii) folding by the Hsp70-Hsp90 cascades. These chaperones prepare their protein clients for folding on their own, without altering their folding path. A particularly interesting role is reserved for Hsp90. The function of Hsp90 in folding is its ancient function downstream of Hsp70, free of cochaperone regulation and present in all kingdoms of life. Eukaryotic signalling networks, however, embrace Hsp90 by a plethora of cochaperones, transforming the profolding machinery to a folding-on-demand factor. We discuss implications for biology and molecular medicine.