The chaperonin TRiC/CCT is a central component of the eukaryotic protein folding machinery and is estimated to fold 5-10% of the eukaryotic proteome. TRiC assembles into a ring-shaped oligomeric complex that is comprised of two stacked rings each containing eight different subunits. The rings create a central cavity where unfolded proteins bind and fold in an ATP dependent manner. A fundamental question remains: how does TRiC recognize and fold a diverse subset of eukaryotic proteins? We hypothesize that each subunit in the hetero-oligomeric complex differs in substrate specificity. However, this hypothesis remains untested, as little is known about the nature of TRiC-substrate interactions. The goal of this proposal is to identify the location of the substrate binding sites in the TRiC subunits and elucidate the mechanisms underlying substrate recognition by TRiC. To this end, we will use a multidisciplinary approach to compare how motifs derived from different TRiC substrates bind to individual TRiC subunits. Understanding TRiC substrate interactions will reveal the mechanism by which this chaperonin facilitates protein folding. This work will have important implications for the development of novel therapeutic approaches to ameliorate diseases associated with protein misfolding.
The eukaryotic chaperonin TRiC plays a fundamental role in the maturation of many important cellular eukaryotic proteins, and its loss-of-function is associated with numerous diseases such as neurodegeneration and cancer. The results of systematically dissecting the chaperonin-substrate binding interactions for diverse substrates in the proposed experiments, will offer directions for therapeutic interventions in these pathologies.
|Leitner, Alexander; Joachimiak, Lukasz A; Bracher, Andreas et al. (2012) The molecular architecture of the eukaryotic chaperonin TRiC/CCT. Structure 20:814-25|