Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies

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Abstract
The interactome of eukaryotic chaperonin TRiC/CCT is identified through a genome-wide approach, revealing an enrichment in large, multidomain proteins, or components of multimeric complexes, rich in hydrophobic sequences and with high β-sheet propensity. Thus, TRiC substrates are slow-folding proteins with complex topology, which are likely to be more prone to aggregation. Folding within the crowded cellular milieu often requires assistance from molecular chaperones that prevent inappropriate interactions leading to aggregation and toxicity. The contribution of individual chaperones to folding the proteome remains elusive. Here we demonstrate that the eukaryotic chaperonin TRiC/CCT (TCP1-ring complex or chaperonin containing TCP1) has broad binding specificity in vitro, similar to the prokaryotic chaperonin GroEL. However, in vivo, TRiC substrate selection is not based solely on intrinsic determinants; instead, specificity is dictated by factors present during protein biogenesis. The identification of cellular substrates revealed that TRiC interacts with folding intermediates of a subset of structurally and functionally diverse polypeptides. Bioinformatics analysis revealed an enrichment in multidomain proteins and regions of β-strand propensity that are predicted to be slow folding and aggregation prone. Thus, TRiC may have evolved to protect complex protein topologies within its central cavity during biosynthesis and folding.