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Protein Folding and Misfolding: A TRiC-ster that Follows the Rules

SBKB [doi:10.1038/sbkb.2015.1]
Featured Article - March 2015
Short description: Experimental and computational techniques establish substrate recognition rules for the chaperonin TRiC.

HIV p6 (teal) binds to a shallow groove in CCT3 (surface representation) via a combination of hydrophobic and electrostatic interactions. Reprinted from 1 Copyright 2014 with permission from Elsevier.

Many proteins need the help of chaperones to fold properly in the cell. TCP-1 ring complex (TRiC), a eukaryotic chaperonin, is required for proper folding of approximately 10% of the proteome, including proteins implicated in cancer, such as p53, von Hippel Lindau tumor suppressor (VHL) and STAT3; in neurologic disorders, such as Huntingtin; and viral proteins, such as the HIV Gag, Vif and p6. How TRiC can interact with structurally and functionally diverse substrates is the question explored by Frydman, Joachimiak and colleagues (PSI HOMEO), through a combination of experimental and computational approaches.

TRiC consists of two eight-membered rings stacked on top of one another. Each of the eight subunits is different but structurally similar, with an ATP-binding domain and an apical substrate-binding domain. The authors used nuclear magnetic resonance to map the binding site of two TRiC subunit-substrate pairs: CCT3 with p6 and CCT1 with a motif from VHL. They created a model of the two complexes using the computational tools CS-Rosetta and RosettaDock. Both substrates bound to a shallow groove formed by helix 11 (H11) and a flexible loop (PL) in each subunit, with interactions governed by hydrophobic residues in the helix and polar residues in the loop.

The authors then investigated the mode of recognition between full-length TRiC and its substrates. They crosslinked TRiC to full-length actin, tubulin or HIV Gag, and identified the binding interfaces by mass spectrometry. Each of the substrates bound to the H11/PL region of various TRiC subunits, and each binding site relied upon a dual recognition mode with a distinct pattern of hydrophobic and polar residues.

This study provides a general set of rules for how TRiC interacts with its varied substrates. The shallow groove between H11 and PL can accommodate a variety of structural motifs, while polar contacts between PL and the substrates may help orient the latter in a manner conducive to folding. While the binding affinity of a single TRiC subunit for the substrate is low, in the context of the full complex, interactions between multiple TRiC subunits and substrates can enable TRiC to differentiate between folded and unfolded proteins.

Jennifer Cable

References

  1. L.A. Joachimiak, T. Walzthoeni, C.W. Liu, R. Aebersold & J. Frydman The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT.
    Cell. 159, 1042-1055 (2014). doi:10.1016/j.cell.2014.10.042

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