Protein Folding by the CCT/TRiC Chaperone Complex

Overview

Journal Curr Opin Struct Biol

Date 2025 Feb 6

PMID 39914052

Authors

Peter S Shen

Barry M Willardson

Affiliations

Soon will be listed here.

Abstract

The chaperonin-containing TCP-1 (CCT) complex, also known as TRiC, is an abundant and essential molecular chaperone responsible for folding a significant portion of the eukaryotic proteome. Prominent CCT folding clients include cytoskeletal proteins such as actin and tubulin, and proteins with β-propeller folds. Recent advances in cryo-EM have provided unprecedented insights into CCT's substrate-specific folding mechanisms. This review summarizes these discoveries, emphasizing how CCT utilizes its unique structural features to recognize and fold diverse substrates.

References

Yam A, Xia Y, Lin H, Burlingame A, Gerstein M, Frydman J . Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nat Struct Mol Biol. 2008; 15(12):1255-62. PMC: 2658641. DOI: 10.1038/nsmb.1515. View

Hein M, Hubner N, Poser I, Cox J, Nagaraj N, Toyoda Y . A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015; 163(3):712-23. DOI: 10.1016/j.cell.2015.09.053. View

Tian G, Vainberg I, Tap W, Lewis S, Cowan N . Specificity in chaperonin-mediated protein folding. Nature. 1995; 375(6528):250-3. DOI: 10.1038/375250a0. View

Cheever M, Snyder J, Gershburg S, Siderovski D, Harden T, Sondek J . Crystal structure of the multifunctional Gbeta5-RGS9 complex. Nat Struct Mol Biol. 2008; 15(2):155-62. PMC: 2702320. DOI: 10.1038/nsmb.1377. View

Minegishi Y, Nakaya N, Tomarev S . Mutation in the Zebrafish cct2 Gene Leads to Abnormalities of Cell Cycle and Cell Death in the Retina: A Model of CCT2-Related Leber Congenital Amaurosis. Invest Ophthalmol Vis Sci. 2018; 59(2):995-1004. PMC: 5815422. DOI: 10.1167/iovs.17-22919. View

Wang Y, Uraki R, Hwang J, Fikrig E . TRiC/CCT Complex, a Binding Partner of NS1 Protein, Supports the Replication of Zika Virus in Both Mammalians and Mosquitoes. Viruses. 2020; 12(5). PMC: 7290343. DOI: 10.3390/v12050519. View

Plimpton R, Cuellar J, Lai C, Aoba T, Makaju A, Franklin S . Structures of the Gβ-CCT and PhLP1-Gβ-CCT complexes reveal a mechanism for G-protein β-subunit folding and Gβγ dimer assembly. Proc Natl Acad Sci U S A. 2015; 112(8):2413-8. PMC: 4345582. DOI: 10.1073/pnas.1419595112. View

Wang S, Sass M, Kwon Y, Ludlam W, Smith T, Carter E . Visualizing the chaperone-mediated folding trajectory of the G protein β5 β-propeller. Mol Cell. 2023; 83(21):3852-3868.e6. PMC: 10841713. DOI: 10.1016/j.molcel.2023.09.032. View

Gestaut D, Zhao Y, Park J, Ma B, Leitner A, Collier M . Structural visualization of the tubulin folding pathway directed by human chaperonin TRiC/CCT. Cell. 2022; 185(25):4770-4787.e20. PMC: 9735246. DOI: 10.1016/j.cell.2022.11.014. View

10.

Jin M, Han W, Liu C, Zang Y, Li J, Wang F . An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity. Proc Natl Acad Sci U S A. 2019; 116(39):19513-19522. PMC: 6765261. DOI: 10.1073/pnas.1903976116. View

11.

Howlett A, Gray A, Hunter J, Willardson B . Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity. J Biol Chem. 2009; 284(24):16386-16399. PMC: 2713520. DOI: 10.1074/jbc.M900800200. View

12.

Alruwaili M, Armstrong S, Prince T, Erdmann M, Matthews D, Luu L . SARS-CoV-2 NSP12 associates with TRiC and the P323L substitution acts as a host adaption. J Virol. 2023; 97(11):e0042423. PMC: 10688337. DOI: 10.1128/jvi.00424-23. View

13.

Meyer A, Gillespie J, Walther D, Millet I, Doniach S, Frydman J . Closing the folding chamber of the eukaryotic chaperonin requires the transition state of ATP hydrolysis. Cell. 2003; 113(3):369-81. DOI: 10.1016/s0092-8674(03)00307-6. View

14.

Roh S, Kasembeli M, Bakthavatsalam D, Chiu W, Tweardy D . Contribution of the Type II Chaperonin, TRiC/CCT, to Oncogenesis. Int J Mol Sci. 2015; 16(11):26706-20. PMC: 4661834. DOI: 10.3390/ijms161125975. View

15.

Geissler S, Siegers K, Schiebel E . A novel protein complex promoting formation of functional alpha- and gamma-tubulin. EMBO J. 1998; 17(4):952-66. PMC: 1170445. DOI: 10.1093/emboj/17.4.952. View

16.

Pavel M, Imarisio S, Menzies F, Jimenez-Sanchez M, Siddiqi F, Wu X . CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat Commun. 2016; 7:13821. PMC: 5155164. DOI: 10.1038/ncomms13821. View

17.

Park J, Kim H, Gestaut D, Lim S, Opoku-Nsiah K, Leitner A . A structural vista of phosducin-like PhLP2A-chaperonin TRiC cooperation during the ATP-driven folding cycle. Nat Commun. 2024; 15(1):1007. PMC: 10837153. DOI: 10.1038/s41467-024-45242-x. View

18.

Zang Y, Jin M, Wang H, Cui Z, Kong L, Liu C . Staggered ATP binding mechanism of eukaryotic chaperonin TRiC (CCT) revealed through high-resolution cryo-EM. Nat Struct Mol Biol. 2016; 23(12):1083-1091. DOI: 10.1038/nsmb.3309. View

19.

Lopez T, Dalton K, Frydman J . The Mechanism and Function of Group II Chaperonins. J Mol Biol. 2015; 427(18):2919-30. PMC: 4706738. DOI: 10.1016/j.jmb.2015.04.013. View

20.

Lukov G, Baker C, Ludtke P, Hu T, Carter M, Hackett R . Mechanism of assembly of G protein betagamma subunits by protein kinase CK2-phosphorylated phosducin-like protein and the cytosolic chaperonin complex. J Biol Chem. 2006; 281(31):22261-22274. DOI: 10.1074/jbc.M601590200. View