Abstract

Recent aspects of molecular chaperone function in health and disease F. Ulrich Hartl Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany While protein folding was originally assumed to occur spontaneously, we now appreciate that in the crowded environment of cells, newly-synthesized polypeptides depend on molecular chaperones to reach their folded states efficiently and at a biologically relevant time scale. Assistance of protein folding is provided by members of different chaperone classes acting to facilitate the interconversion of folding intermediates, preventing misfolding and off-pathway aggregation, often in an ATP -dependent mechanism. A well-studied example are the cylindrical chaperonins (GroEL/ES in bacteria, Hsp60 in mitochondria, TRiC in the eukaryotic cytosol), which form nano-cages for single protein molecules to fold unimpaired by aggregation. As an added benefit, encapsulation results in entropic confinement of dynamic folding intermediates, thereby markedly accelerating folding for some proteins over the spontaneous folding rate.

Once folded, many proteins continue to require chaperone surveillance to retain their functional states, especially under conditions of cell stress. Failure of the chaperone machinery to maintain proteostasis, i.e. the conformational integrity and balance of the cellular proteome, facilitates the manifestation of diseases in which proteins misfold and form toxic aggregates. These disorders include, among others, Alzheimer’s, Parkinson’s, and Huntington’s disease.

I will provide an overview of chaperone mechanisms and then discuss recent work providing new insights into the role of chaperones in protein folding and proteostasis maintenance, with a focus on observations in intact cells.