The long term goal of this project is to understand how the chaperonin TRiC (also called CCT) mediates protein folding. Chaperonins are essential components of the cellular folding machinery. These large protein complexes, consisting of two stacked seven- to nine-membered rings, bind unfolded substrates in their central cavity and use binding and hydrolysis of ATP to mediate polypeptide folding. The folding of substrate proteins occurs in the central cavity formed by each ring. There are substantial differences between group I chaperonins, found in prokaryotic cells, and the distantly related group II chaperonins in Archaea and Eukarya. Group I chaperonins require a ring-shaped cofactor, such GroES for GroEL, that upon binding acts as a lid for the cavity, creating a folding chamber that encloses polypeptide substrates. Group II chaperonins are hetero-oligomeric and lack a GroES-like cofactor, suggesting that their conformational cycle is significantly different from group I chaperonins. The present proposal aims to elucidate the mechanism of the eukaryotic chaperonin TRiC (TCP1-Ring Complex, also called CCT). Despite its essential role in polypeptide folding, little is known about the mechanism and substrate binding properties of TRiC. To understand how TRiC facilitates folding we propose the following specific aims: 1. Characterize of the nucleotide cycle of the chaperonin TRiC 2. Define the molecular basis of TRiC-substrate interactions 3. Investigate the mechanism of TRiC-assisted substrate folding.

Public Health Relevance

The eukaryotic chaperonin TRiC is a ring-shaped hetero-oligomeric complex that folds many essential cellular proteins in an ATP-dependent manner. This project aims to understand the mechanism of TRiC-mediated folding. Recent observations have highlighted the links between TRiC and several pathological states including cancer and neurodegeneration. Thus our project will help deciphering the role of this chaperonin in cellular folding and provide therapies to ameliorate human misfolding disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-B (02))
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Wehrle, Janna P
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Stanford University
Schools of Arts and Sciences
United States
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Sontag, Emily M; Vonk, Willianne I M; Frydman, Judith (2014) Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr Opin Cell Biol 26:139-46
Joachimiak, Lukasz A; Walzthoeni, Thomas; Liu, Corey W et al. (2014) The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT. Cell 159:1042-55
Sontag, Emily M; Joachimiak, Lukasz A; Tan, Zhiqun et al. (2013) Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes. Proc Natl Acad Sci U S A 110:3077-82
Leitner, Alexander; Joachimiak, Lukasz A; Bracher, Andreas et al. (2012) The molecular architecture of the eukaryotic chaperonin TRiC/CCT. Structure 20:814-25
Douglas, Nicholai R; Reissmann, Stefanie; Zhang, Junjie et al. (2011) Dual action of ATP hydrolysis couples lid closure to substrate release into the group II chaperonin chamber. Cell 144:240-52
Kim, So Yeon; Miller, Erik J; Frydman, Judith et al. (2010) Action of the chaperonin GroEL/ES on a non-native substrate observed with single-molecule FRET. J Mol Biol 401:553-63
Pan, Xuewen; Reissman, Stefanie; Douglas, Nick R et al. (2010) Trivalent arsenic inhibits the functions of chaperonin complex. Genetics 186:725-34
Tam, Stephen; Spiess, Christoph; Auyeung, William et al. (2009) The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation. Nat Struct Mol Biol 16:1279-85
Booth, Christopher R; Meyer, Anne S; Cong, Yao et al. (2008) Mechanism of lid closure in the eukaryotic chaperonin TRiC/CCT. Nat Struct Mol Biol 15:746-53
Reissmann, Stefanie; Parnot, Charles; Booth, Christopher R et al. (2007) Essential function of the built-in lid in the allosteric regulation of eukaryotic and archaeal chaperonins. Nat Struct Mol Biol 14:432-40

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