Environmental Molecular Sciences Laboratory

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Structure and function of the Gbeta5-CCT complex

Date: 
Sunday, November 15, 2020
Principal Investigator: 
Peter Shen
Lead Institution: 
University of Utah
Project ID: 
51709
Abstract: 

The cytosolic chaperonin CCT is a large, 1 MDa protein folding machine that plays a central role in maintaining the cellular proteome. CCT contributes to proteome homeostasis by assisting in the folding of a large set of proteins with complex folds and multiple domains. Proper CCT function is therefore essential to many cellular functions. Inactivating mutations in CCT are known to cause Leber Congenital Amaurosis (LCA). Yet, little is known about how CCT contributes to the visual process. The Willardson lab has made important contributions to understanding the function of CCT in photoreceptor cells by discovering that CCT and its co-chaperone phosducin-like protein 1 (PhLP1) assist in the folding of the G protein beta1 (Gbeta1) and beta5 (Gbeta5) subunits and their assembly into dimers with the G protein beta1 subunit (Gbeta1) and regulators of G protein signaling 9 (RGS9) proteins, respectively. In fact, the LCA caused by inactivating CCT mutations may stem from an inability to fold these proteins that play such essential roles in vision. Despite the importance of CCT in maintaining protein homeostasis, we know very little at the molecular level about how CCT assists in the folding substrates and how mutations disrupt folding and cause disease. To address this gap in knowledge, the Shen and Willardson labs are collaborating to determine the structures of key intermediates in the folding of human Gbeta5. If successful, these structures will reveal principles of how CCT folds its client substrates.