Folding of Proteins in Vivo Is Promoted by Chaperones

Although protein folding occurs in vitro, only a minority of unfolded molecules undergo complete folding into the native conformation within a few minutes. Clearly, cells require a faster, more efficient mechanism for folding proteins into their correct shapes; otherwise, cells would waste much energy in the synthesis of nonfunctional proteins and in the degradation of misfolded or unfolded proteins. Indeed, more than 95 percent of the proteins present within cells have been shown to be in their native conformation, despite high protein concentrations (200-300 mg/ml), which favor the precipitation of proteins in vitro.

The explanation for the cell's remarkable efficiency in promoting protein folding probably lies in chaperones, a class of proteins found in all organisms from bacteria to humans. Chaperones are located in every cellular compartment, bind a wide range of proteins, and function in the general protein-folding mechanism of cells. Two general families of chaperones are reconized:

■ Molecular chaperones, which bind and stabilize unfolded or partly folded proteins, thereby preventing these proteins from aggregating and being degraded

■ Chaperonins, which directly facilitate the folding of proteins

Molecular chaperones consist of Hsp70 and its homologs: Hsp70 in the cytosol and mitochondrial matrix, BiP in the endoplasmic reticulum, and DnaK in bacteria. First identified by their rapid appearance after a cell has been stressed by heat shock, Hsp70 and its homologs are the major chaperones in all organisms. (Hsc70 is a constitutively expressed homolog of Hsp70.) When bound to ATP, Hsp70-like proteins assume an open form in which an exposed hydrophobic pocket transiently binds to exposed hydrophobic regions of the unfolded target protein. Hydrolysis of the bound ATP causes molecular chaperones to assume a closed form in which a target protein can undergo folding. The exchange of ATP for ADP releases the target protein (Figure 3-11a, top). This cycle is



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