Paul Adams Research Group
Chaperones are a family of proteins that assist in many essential cell processes: the assembly of macromolecular structures; the transition of partially folded, misfolded, or newly synthesized proteins to the native state; and the channeling of misfolded proteins to the degradation proteosome. They are present in all cell components, and in every organism. In eukaryotes, an estimated 5-10% of cytosolic proteins rely on chaperones for proper folding. The importance of chaperone function is further highlighted by the range of diseases that result from misfolded, aggregated or stress-denatured proteins, from neurodegenerative disorders such as Huntingtons and Alzheimers, to prion diseases and cancer. In addition, recent promising antiviral drug discovery efforts have been aimed at modulating chaperone activity in the cell.
These versatile proteins are classified according to function, size and location in the cell. The subclass termed chaperonins are mega-dalton complexes composed of two stacked rings of 7-8 subunits each. Chaperonins are further delineated based on their requirements for co-chaperones and their evolutionary branch. The group I chaperonins, such as the well-studied GroEL from E. coli, are found in bacterial cytoplasm and in eukaryotic mitochondria and plant chloroplasts. These proteins require a separate 'lid' protein for full functionality, while the group II chaperonins, such as the eukaryotic TRiC, are found in Archaea and the eukaryotic cytosol, and contain a built-in lid.
The protein-folding chambers of chaperonins open and close in an ATP-dependent manner, and exhibit both positive intra-ring and negative inter-ring cooperativity. Although the ATP binding sites in group I and group II chaperonins are structurally similar, the conformation changes induced by ATP binding and hydrolysis are quite distinct. Despite extensive biochemical and structural work, much remains unknown about chaperonin function, such as the mechanisms of substrate recognition, and the way in which ATP hydrolysis drives changes in the protein conformation and movement of substrate within the chamber.
Working in collaboration with the Judith Frydman and the Jonathan King laboratories, Adams's group is working on addressing these questions through structural studies of the group II chaperonins from Methanococcus maripaludis.
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