Due to the crowded envirnoment within the cell, many proteins must interact with molecular chaperones to attain their native conformation (reviewed in Young et al., 2004). Chaperones recognize and associate with proteins in their non-native state and facilitate their folding by stabilizing the conformation of productive folding intermediates. Chaperones that take part broadly in de novo protein folding, such as the Hsp70s and the chaperonins, facilitate the folding process through cycles of substrate binding and release regulated by their ATPase activity (see Young et al., 2004; Spiess et al., 2004; Bigotti and Clarke, 2008).
View original pathway at Reactome.
Freund A, Zhong FL, Venteicher AS, Meng Z, Veenstra TD, Frydman J, Artandi SE.; ''Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1.''; PubMedEurope PMCScholia
Litterman N, Ikeuchi Y, Gallardo G, O'Connell BC, Sowa ME, Gygi SP, Harper JW, Bonni A.; ''An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning.''; PubMedEurope PMCScholia
Kubota H, Hynes GM, Kerr SM, Willison KR.; ''Tissue-specific subunit of the mouse cytosolic chaperonin-containing TCP-1.''; PubMedEurope PMCScholia
Naletova IN, Popova KM, Eldarov MA, Kuravsky ML, Schmalhausen EV, Sevostyanova IA, Muronetz VI.; ''Chaperonin TRiC assists the refolding of sperm-specific glyceraldehyde-3-phosphate dehydrogenase.''; PubMedEurope PMCScholia
Lukov GL, Baker CM, Ludtke PJ, Hu T, Carter MD, Hackett RA, Thulin CD, Willardson BM.; ''Mechanism of assembly of G protein betagamma subunits by protein kinase CK2-phosphorylated phosducin-like protein and the cytosolic chaperonin complex.''; PubMedEurope PMCScholia
Bigotti MG, Clarke AR.; ''Chaperonins: The hunt for the Group II mechanism.''; PubMedEurope PMCScholia
Tian G, Lewis SA, Feierbach B, Stearns T, Rommelaere H, Ampe C, Cowan NJ.; ''Tubulin subunits exist in an activated conformational state generated and maintained by protein cofactors.''; PubMedEurope PMCScholia
Lu J, Chiang J, Iyer RR, Thompson E, Kaneski CR, Xu DS, Yang C, Chen M, Hodes RJ, Lonser RR, Brady RO, Zhuang Z.; ''Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.''; PubMedEurope PMCScholia
Young JC, Agashe VR, Siegers K, Hartl FU.; ''Pathways of chaperone-mediated protein folding in the cytosol.''; PubMedEurope PMCScholia
Yam AY, Xia Y, Lin HT, Burlingame A, Gerstein M, Frydman J.; ''Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies.''; PubMedEurope PMCScholia
Won KA, Schumacher RJ, Farr GW, Horwich AL, Reed SI.; ''Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT.''; PubMedEurope PMCScholia
Bhamidipati A, Lewis SA, Cowan NJ.; ''ADP ribosylation factor-like protein 2 (Arl2) regulates the interaction of tubulin-folding cofactor D with native tubulin.''; PubMedEurope PMCScholia
Lai CW, Kolesnikov AV, Frederick JM, Blake DR, Jiang L, Stewart JS, Chen CK, Barrow JR, Baehr W, Kefalov VJ, Willardson BM.; ''Phosducin-like protein 1 is essential for G-protein assembly and signaling in retinal rod photoreceptors.''; PubMedEurope PMCScholia
Lukov GL, Hu T, McLaughlin JN, Hamm HE, Willardson BM.; ''Phosducin-like protein acts as a molecular chaperone for G protein betagamma dimer assembly.''; PubMedEurope PMCScholia
Tracy CM, Kolesnikov AV, Blake DR, Chen CK, Baehr W, Kefalov VJ, Willardson BM.; ''Retinal cone photoreceptors require phosducin-like protein 1 for G protein complex assembly and signaling.''; PubMedEurope PMCScholia
Guenther MG, Yu J, Kao GD, Yen TJ, Lazar MA.; ''Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex.''; PubMedEurope PMCScholia
Howlett AC, Gray AJ, Hunter JM, Willardson BM.; ''Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity.''; PubMedEurope PMCScholia
Wells CA, Dingus J, Hildebrandt JD.; ''Role of the chaperonin CCT/TRiC complex in G protein betagamma-dimer assembly.''; PubMedEurope PMCScholia
Miyata Y, Shibata T, Aoshima M, Tsubata T, Nishida E.; ''The molecular chaperone TRiC/CCT binds to the Trp-Asp 40 (WD40) repeat protein WDR68 and promotes its folding, protein kinase DYRK1A binding, and nuclear accumulation.''; PubMedEurope PMCScholia
Tian G, Thomas S, Cowan NJ.; ''Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity.''; PubMedEurope PMCScholia
Zebol JR, Hewitt NM, Moretti PA, Lynn HE, Lake JA, Li P, Vadas MA, Wattenberg BW, Pitson SM.; ''The CCT/TRiC chaperonin is required for maturation of sphingosine kinase 1.''; PubMedEurope PMCScholia
Spiess C, Meyer AS, Reissmann S, Frydman J.; ''Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets.''; PubMedEurope PMCScholia
Trinidad AG, Muller PA, Cuellar J, Klejnot M, Nobis M, Valpuesta JM, Vousden KH.; ''Interaction of p53 with the CCT complex promotes protein folding and wild-type p53 activity.''; PubMedEurope PMCScholia
Kasembeli M, Lau WC, Roh SH, Eckols TK, Frydman J, Chiu W, Tweardy DJ.; ''Modulation of STAT3 folding and function by TRiC/CCT chaperonin.''; PubMedEurope PMCScholia
Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003). In the case of CCT-mediated tubulin folding, one or more rounds of ATP hydrolysis are likely required before the association of non-exchangeable GTP with chaperonin-bound alpha tubulin.
Factor A:beta tubulin complex act as a reservoir capable of accepting or delivering its target tubulin protein to cofactor D (Tian et al., 1997). In the reverse reaction, Cofactor A may displace cofactor D in a cofactor D:beta tubulin complex.
Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by tubulin-specific chaperones A and D (TBCA and TBCD) (Tian et al. 1996, Tian et al. 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. TBCD is involved in the tubulin-folding pathway, acting as a GTPase activating protein (GAP) for beta-tubulin. The ADP-ribosylation factor-like protein 2 (ARL2) is able to down-regulate TBCD specifically, thus preventing microtuble disruption (Bhamidipati et al. 2000, Tian et al. 2010).
The factor B:alpha tubulin complex act as a reservoir capable of accepting or delivering alpha tubulin to cofactor E (Tian et al., 1997). In the reverse reaction, cofactor B may displace cofactor E in the cofactor E:alpha tubulin complex.
Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by tubulin-specific chaperones A and D (TBCA and TBCD) (Tian et al. 1996, Tian et al. 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. TBCD is involved in the tubulin-folding pathway, acting as a GTPase activating protein (GAP) for beta-tubulin. The ADP-ribosylation factor-like protein 2 (ARL2) is able to down-regulate TBCD specifically, thus preventing microtuble disruption (Bhamidipati et al. 2000, Tian et al. 2010).
Unfolded actins and tubulins compete efficiently for binding to TriC/CCT and their chaperonin binding sites appear to be at least in part overlapping (Melki et al., 1993).
Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin.
Beta tubulin within the active (Factor E:alpha tubulin: Factor D:beta tubulin:Factor C )-supercomplex hydrolyzes GTP. This results in the dissociation of the complex and the release of the native tubulin heterodimer (Tian et al., 1997).
Factor E:alpha tubulin and Factor D:beta tubulin interact with each other in a reversible reaction to form the complex (Factor E alpha tubulin:Factor D:beta tubulin) (Tian et al., 1997).
Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin.
During the synthesis of actin and tubulin, the nascent ribosome-associated chains bind to the heteromeric chaperone protein, prefoldin (PFD) (Hansen et al., 1999).
TriC/CCT-mediated beta-actin folding involves rapid ATP-independent formation of a binary complex, followed by a slower ATP-dependent release of the native product (Gao et al., 1992). Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003).
A combination of proteomic and bioinformatics analyses of TRiC substrates has revealed that they have complex topologies that are slow folding and aggregation prone (Yam et al., 2008). These substrates are also enriched in proteins that belong to oligomeric assemblies suggesting that TRiC plays a role in promoting complex assembly (Yam et al., 2008). Two possible mechanisms describing the role of TriC have been suggested (Yam et al., 2008). The processes of TRiC-mediated folding and assembly could be directly coupled, or TRiC could fold monomeric subunits and hold them in an assembly-competent state until they associate with the appropriate partner subunits. The complete list of TriC subsrates is not yet known. Many of its substrates that are targeted during biosynthesis are conserved between mammals and yeast (Yam et al. 2008).
The TRiC/CCT chaperonin complex binds nascent, unfolded, G-protein beta subunit (GNB1, GNB2, GNB3, GNB4 or GNB5) (Wells et al. 2006). G-beta reaches a near-native state in the folding cavity of TRiC, except that TRiC cannot mediate the folding of the seven-bladed beta propeller of the G-protein beta to a stable conformation (Plimpton et al. 2015).
In an ATP-dependent process, G-beta reaches a near-native state in the folding cavity of TRiC, except that TRiC cannot mediate the folding of the seven-bladed beta propeller of the G-protein beta to a stable conformation (Plimpton et al. 2015).
PDCL (PhLP1), phosphorylated by the casein kinase II complex (CK2), simultaneously binds to the unfolded G-protein beta subunit and the TRiC/CCT chaperonin (Lukov et al. 2005, Lukov et al. 2006, Plimpton et al. 2015). Phosphorylation is not a prerequisite for PDCL binding to TRiC/CCT and the unfolded G-protein beta, but is necessary for PDCL-mediated release of folded G-protein beta from TRiC/CCT (Lukov et al. 2006).
Based on structural studies of the TRiC/CCT chaperonin complex, the exchange of ADP for ATP enables conformational change of the chaperonin complex needed for folding of substrate proteins. It is assumed that TRiC/CCT-mediated folding of the G-protein beta subunit follows this universal pattern of TRiC/CCT functioning (Melki et al. 1997).
The casein kinase II (CK2) complex phosphorylates PDCL (PhLP1) at the N-terminal serine residues S18, S19, S20 and S25. The phosphorylation at S20 is the most critical for PDCL-mediated folding of the G-protein beta subunit (Lukov et al. 2005, Lukov et al. 2006).
G-protein gamma subunit binds folded G-protein beta subunits 1-4 associated with PDCL (PhLP1) after release from TRiC/CCT, resulting in formation of the G-protein beta:gamma complex (Lukov et al. 2006, Plimpton et al. 2015). In Pdcl-depleted mouse rods, G-protein beta:gamma dimer formation is decreased 50-fold, leading to 10-fold reduction in light sensitivity (Lai et al. 2013).
PDCL (PhLP1) enables completion of folding of G-protein beta subunits 1-4 (GNB1, GNB2, GNB3 and GNB4) by the TRiC/CCT chaperonin, resulting in the release of dimers of PDCL and folded G-protein beta 1-4 (Lukov et al. 2005, Lukov et al. 2006, Howlett et al. 2009, Plimpton et al. 2015).
RGS proteins RGS7, RGS9 and, probably RGS6 and RGS11, bind to folded G-protein beta 5 subunit (GNB5) associated with the CCT/TRiC chaperonin. A RGS protein can associate with GNB5 and CCT/TRiC only after PDCL (PhLP1) is released as PDCL and RGS protein interact with overlapping regions of GNB5 (Howlett et al. 2009, Tracy et al. 2015).
PDCL (PhLP1) increases stability of the G-protein beta 5 subunit (GNB5), presumably by assisting with the proper folding of GNB5, but does not release folded GNB5 from the TRiC/CCT chaperonin (Howlett et al. 2009).
Dimers of folded G-protein beta 5 subunit (GNB5) and a RGS protein RGS7, RSG9, and probably RGS6 or RGS11, are released from the CCT/TRiC chaperonin complex (Howlett et al. 2009, Tracy et al. 2015).
G-protein alpha associates with G-protein beta:gamma dimers bound to PDCL (PhLP1), resulting in release of the G-protein heterotrimer from PDCL co-chaperone (Lukov et al. 2005, Plimpton et al. 2015).
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DataNodes
folding
intermediatefolding
intermediatefolded G-protein beta
subunit:CCT/TRiC:ADPG-protein beta
subunit:CCT/TRiC:ADPG-protein beta
subunit:CCT/TRiC:ATPtubulin:GTP: Cofactor D:alpha
tubulin:GTP:Cofactor EA:GTP:beta-tubulin folding
intermediatesubstrate
candidatesAnnotated Interactions
folding
intermediatefolding
intermediatefolding
intermediatefolding
intermediatefolded G-protein beta
subunit:CCT/TRiC:ADPfolded G-protein beta
subunit:CCT/TRiC:ADPG-protein beta
subunit:CCT/TRiC:ADPG-protein beta
subunit:CCT/TRiC:ADPG-protein beta
subunit:CCT/TRiC:ATPG-protein beta
subunit:CCT/TRiC:ATPtubulin:GTP: Cofactor D:alpha
tubulin:GTP:Cofactor Etubulin:GTP: Cofactor D:alpha
tubulin:GTP:Cofactor EA:GTP:beta-tubulin folding
intermediateA:GTP:beta-tubulin folding
intermediatesubstrate
candidates