Medical Genetics Branch,

nhgri.nih.gov The native (correctly folded) state of a protein is required for biological activity and is predominantly determined by the primary structure, or amino acid sequence1. Successful protein folding is a multistep process of conformal fluctuation yielding transition states of lower free energy and generation of the native structure2. However, cellular conditions can favor non-productive folding and aggregation of polypeptide chains because of macromolecular crowding, incomplete availability of entire folding domains owing to the sequential nature of translation and the exposure of slow-folding, hydrophobic domains during translation3. To reduce protein aggregation, cellular mechanisms have evolved, such as co-translational domain folding for eukaryotic proteins with multiple domains4 and the chaperone class of proteins5. Chaperones A chaperone is a protein that selectively recognizes and binds to the exposed hydrophobic surfaces of a non-native protein in a noncovalent interaction in order to inhibit irreversible aggregation. Release of the polypeptide is commonly driven by an ATP-dependent conformational change of the chaperone, permitting subsequent folding of the non-native protein. Chaperones therefore prevent protein aggregation and facilitate the correct folding of non-native proteins through regulated binding and release in vivo (Refs 5–9). There are several different classes of chaperones defined by molecular size, cellular compartment and function (Table 1). The largest chaperone families are Hsp90 (heat shock protein of apparen