The Human Mitochondrial Chaperonin: It Takes Two Single-Rings to Tango

The human mitochondrial chaperonin is a macromolecular machine that catalyzes the proper folding and assembly of newly imported mitochondrial proteins into their biologically active state. It is composed of two proteins from the highly conserved heat shock protein family, hsp10 and hsp60, that assemble into large oligomeric complexes responsible for mediating the folding of non-native polypeptides in an ATP dependent manner. In addition to its innate role in protein folding, human mitochondrial hsp60 has been implicated in numerous moonlighting cellular activities that have been linked to diseases conditions such as cancer and neurodegeneracy. In light of its cellular importance, the conditions that propel the human mitochondrial chaperonin through its protein folding mechanism are not well understood. Here I propose a protein folding scheme for the mitochondrial chaperonin based on negative stain electron microscopy 3-D reconstructions. I found that the human mitochondrial chaperonin complex accommodates both analogous and novel conformations to the bacterial chaperonin groEL/ES under the electron microscope. In addition, I report the first 3-D reconstruction of the human mitochondrial hsp60/10 single ring complex, an intermediate not observed in the groEL/ES protein folding mechanism. Collectively these results provide insight into the architecture of the human mitochondrial chaperonin along its protein folding pathway and lay the foundation for high-resolution structural investigations