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.
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The authors thank members of the Frydman laboratory and R. Andino for comments and discussion. The cDNA library was a generous gift from W. Zhao and G. Fang (Department of Biology, Stanford University). We thank W. Harper (Department of Pathology, Harvard Medical School), T. Kinzy (Department of Molecular Genetics & Microbiology, Rutgers University), and Michael Rexach (Department of Biological Sciences, Stanford University) for gifts of plasmids and antibodies. This work was supported by grants from the US National Institutes of Health and the W.M. Keck Foundation.
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Yam, A., Xia, Y., Lin, H. et al. Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nat Struct Mol Biol 15, 1255–1262 (2008). https://doi.org/10.1038/nsmb.1515
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