Many proteins cannot exist in the cell without their binding partners.  These protein complexes often require the help of other proteins, called chaperones, to bring the complexes together.  This is certainly the case for protein complexes involved in cell signaling processes.  Our work has focused on the mechanism of assembly of two types of signaling complexes, the G protein heterotrimer and the mTOR kinase complexes.  It is through the G protein complex and its associated receptors and effectors that cells detect hormones, neurotransmitters, chemokines and sensory signals such as odorants, taste molecules and even photons of light.  G proteins regulate almost every aspect of cellular physiology and as a result more than a third of current therapeutic drugs target G protein signaling pathways.  The two mTOR complexes, mTORC1 and mTORC2, are also high-value drug targets because of their role in orchestrating cell survival, growth and metabolism in response to growth hormones and nutrient levels.

Both G protein and mTOR complexes are assembled with the help of the cytosolic chaperonin CCT (also called TRiC), a large protein folding machine with a double-ring structure of eight different chaperonin subunits in each ring.  The center of each ring creates a protein folding chamber in which nascent proteins with intricate folding trajectories bind and are assisted in the folding process. One such protein fold is the β-propeller, which commonly has seven β-sheets that form the blades of a propeller-like circular structure. β-propellers have a unique folding trajectory that requires the C-terminus to interact with the N-terminus to make the last β-sheet that closes the b-propeller.  CCT is believed to facilitate this process.  We have found that the β-propellers of the G protein β subunit (Gβ) and the mLST8 and Raptor subunits of mTOR complexes are folded by CCT prior to their assembly into complexes.