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Symmetry-free cryo-EM structures of the chaperonin TRiC along its ATPase-driven conformational cycle.

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Cong Y, Schröder GF, Meyer AS, Jakana J, Ma B, Dougherty MT, Schmid MF, Reissmann S, Levitt M, Ludtke SL, Frydman J, Chiu W
OpenAccess logo EMBO J 31 720-30 (2012)
Related entries: 4a0o, 4a0v, 4a13

Cited: 60 times
EuropePMC logo PMID: 22045336

Abstract

The eukaryotic group II chaperonin TRiC/CCT is a 16-subunit complex with eight distinct but similar subunits arranged in two stacked rings. Substrate folding inside the central chamber is triggered by ATP hydrolysis. We present five cryo-EM structures of TRiC in apo and nucleotide-induced states without imposing symmetry during the 3D reconstruction. These structures reveal the intra- and inter-ring subunit interaction pattern changes during the ATPase cycle. In the apo state, the subunit arrangement in each ring is highly asymmetric, whereas all nucleotide-containing states tend to be more symmetrical. We identify and structurally characterize an one-ring closed intermediate induced by ATP hydrolysis wherein the closed TRiC ring exhibits an observable chamber expansion. This likely represents the physiological substrate folding state. Our structural results suggest mechanisms for inter-ring-negative cooperativity, intra-ring-positive cooperativity, and protein-folding chamber closure of TRiC. Intriguingly, these mechanisms are different from other group I and II chaperonins despite their similar architecture.

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  1. Molecular chaperone functions in protein folding and proteostasis. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Annu Rev Biochem 82 323-355 (2013)
  2. Chaperone machines for protein folding, unfolding and disaggregation. Saibil H. Nat Rev Mol Cell Biol 14 630-642 (2013)
  3. The Mechanism and Function of Group II Chaperonins. Lopez T, Dalton K, Frydman J. J Mol Biol 427 2919-2930 (2015)
  4. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. Hu C, Yang J, Qi Z, Wu H, Wang B, Zou F, Mei H, Liu J, Wang W, Liu Q. MedComm (2020) 3 e161 (2022)
  5. Contribution of the Type II Chaperonin, TRiC/CCT, to Oncogenesis. Roh SH, Kasembeli M, Bakthavatsalam D, Chiu W, Tweardy DJ. Int J Mol Sci 16 26706-26720 (2015)
  6. ATP-driven molecular chaperone machines. Clare DK, Saibil HR. Biopolymers 99 846-859 (2013)
  7. The ATP-powered gymnastics of TRiC/CCT: an asymmetric protein folding machine with a symmetric origin story. Gestaut D, Limatola A, Joachimiak L, Frydman J. Curr Opin Struct Biol 55 50-58 (2019)
  8. Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease. Rodriguez A, Von Salzen D, Holguin BA, Bernal RA. Front Mol Biosci 7 159 (2020)
  9. The TRiCky Business of Protein Folding in Health and Disease. Ghozlan H, Cox A, Nierenberg D, King S, Khaled AR. Front Cell Dev Biol 10 906530 (2022)
  10. Asymmetric perturbations of signalling oligomers. Maksay G, Tőke O. Prog Biophys Mol Biol 114 153-169 (2014)
  11. Enzymatic and synthetic regulation of polypeptide folding. Muraoka T, Okumura M, Saio T. Chem Sci 15 2282-2299 (2024)

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