Many proteins are dependent upon chaperones to properly fold. Failure to fold correctly is associated with many diseases including cancer and aging associated neurodegenerative disorders. While most chaperones are redundant in function, TRiC and its homologous chaperonins are essential in all kingdoms. All eukaryotic chaperonins are composed of two rings stacked back to back, each formed by 7-9 subunits that produce a central cavity that encapsulates substrates. TRiC-mediated folding is driven by ATP binding and hydrolysis, which regulate its conformational cycle. While progress has been made in understanding the mechanism of simpler homo-oligomeric archaeal chaperonins, the mechanism of folding by the eukaryotic chaperonin, TRiC, which is composed of eight paralogous subunits, has remained elusive. Importantly, the divergence of the subunits has provided unique folding properties allowing TRiC to fold essential eukaryotic substrates that the homologous chaperonins are incapable of folding. TRiC is also assisted by the hetero-hexameric cochaperone Prefoldin, which is thought to transfer non-natively folded substrates to TRiC. The goal of this proposal is to study mechanistic, functional and structural aspects of the ATP-dependent conformational cycle of TRiC and the mechanisms of TRiC substrate-recognition;I also aim to define whether and how these TRiC functions are modulated by Prefoldin. The Frydman lab has developed a system in yeast that allows replacement of any of the TRiC subunits with the same subunit containing lethal mutations, and has extensive experience and tools to address these questions in vivo and in vitro.

Public Health Relevance

Most proteins are dependent upon molecular machines, termed chaperones, to reach a properly folded functional state. These same factors also assist in preventing and resolving the aggregation of proteins linked to many disease states. The goal of this proposal is to further our understanding of how these chaperones recognize and fold their substrates.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM103124-03
Application #
8725199
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hoodbhoy, Tanya
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304