Proper three-dimensional structure of proteins is paramount to their function, and misfolded proteins not only lead to loss of that function but to aggregates that can disrupt cellular processes. In ideal conditions, proteins fold spontaneously into their native three-dimensional structures, driven by their amino acid sequence (Ellis, 1999). However, in the crowded and stressed environment of the cell, assistance is often required to avoid misfolding and aggregation. This week we highlight heat shock protein 60 (HSP60), pictured here in the mitochondria of U2OS cells. As a member of the class 1 chaperonin family, HSP60 assists in the folding of newly translated, imported, or denatured proteins in the mitochondrial matrix, particularly under conditions of stress such as high temperatures or UV light ( Hartl, 1996).

Like its chloroplast and bacterial homologs, HSP60 consists of two heptameric rings stacked back-to-back, forming a barrel-like structure that encapsulates a cavity ideal for protein folding ( Ranford et al, 2000). The activity of HSP60 is mediated by ATP hydrolysis, which triggers conformational changes that allow for alternation between hydrophilic and hydrophobic substrate binding sites. In its binding-active state, HSP60 presents a flexible hydrophobic opening that likely binds nonnative species through exposed hydrophobic surfaces that in the native state are buried ( Bukau et al, 1998). Binding of ATP as well as a lid-like co-chaperonin, HSP10, triggers enlargement of the central channel and ingression of the unfolded protein ( Levy-Rimler et al, 2001). Undisturbed by the distracting molecular interactions of the outside and encouraged by the hydrophilic channel walls, which favor burial of hydrophobic surfaces, the sequestered protein is allowed to curl into its proper structure. A final ATP-dependent alternation triggers its release back into the mitochondrial matrix.

Through this cycle, HSP60 is an invaluable component of our protein machinery, and contributes to the function and homeostasis in our cells even in conditions of high cellular stress.