Molecular Chaperone Functions of Heat-Shock Proteins

Molecular chaperones, many of them so-called heat-shock or stress proteins (hsps), have emerged over recent years as an important topic in cell biology. The functions of these proteins under normal cellular conditions as well as under conditions of stress are the focus of intensive research activity of cell biologists, biochemists, and, more recently, biophysicists. From the wealth of studies available to date, it appears that the major importance of molecular chaperones lies in the area of protein folding. The long-held view that newly synthesized proteins in the cell fold in a largely spontaneous process has been called into question. Although the basic principle that the primary sequence of a protein is sufficient to specify its three-dimensional structure remains unchallenged, protein folding in cells, as opposed to the test tube, depends on helper proteins. In this review we focus on the function of the major hsp70, hsp60, and hsp90 classes of molecular chaperones, emphasizing the functional cooperation between different chaperones and their interactions with specific regulatory proteins. We summarize the major lines of evidence that molecular chaperones are involved in a multitude of processes, in different cellular compartments, wherever the folded state of proteins has to be achieved de novo, stabilized under stress conditions, or modulated to regulate their activity state. Our discussion also includes the recently discovered chaperones of the TCP1 family, which may have hsp60-like functions in the eukaryotic cytosol. For an overview of the functions of other non-heat-shock chaperone systems, the reader may be referred to recent articles by Gething & Sambrook and Freedman.