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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074074-08
Application #
8511691
Study Section
Special Emphasis Panel (ZRG1-CB-B (02))
Program Officer
Wehrle, Janna P
Project Start
2005-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$387,719
Indirect Cost
$145,395
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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
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Reissmann, Stefanie; Joachimiak, Lukasz A; Chen, Bryan et al. (2012) A gradient of ATP affinities generates an asymmetric power stroke driving the chaperonin TRIC/CCT folding cycle. Cell Rep 2:866-77

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