Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_550


 Cct1;  TCP-1

Historical Background

In the cell, the correct folding of many proteins depends on the function of preexisting ones known as molecular chaperones (for a review see Hartl and Hayer-Hartl 2009). These, were defined as proteins that bind to and stabilize an otherwise unstable conformation of another protein, and by controlling binding and release, facilitate its correct fate in vivo, be it folding, oligomeric assembly, transport to a particular subcellular compartment, or disposal by degradation. Molecular chaperones do not convey steric information specifying correct folding: instead, they prevent incorrect interactions within and between nonnative peptides, thus typically increasing the yield but not the rate of folding reactions.

Molecular chaperones are ubiquitous and comprise several protein families that are structurally unrelated (Hartl and Hayer-Hartl 2009). The Hsp70s and the Chaperonin families have been extensively studied. Hsp70 homologs are widespread in prokaryotes and eukaryotes where they occur in the cytosol, mitochondria, chloroplasts, and endoplasmic reticulum. Their expression can be induced by a variety of cellular stresses, but they have also essential functions under normal cellular conditions. Chaperonins are large oligomers and have ring-like or toroidal structures with central cavities. Group I chaperonins are found in Eubacteria (the chaperonin of E. coli GroEL and its co-chaperonin GroES), and their close homologs in mitochondria (Hsp60-Hsp10) and chloroplasts (cpn60-cpn10), eukaryotic organelles of endosymbiotic origin. The eukaryotic cytosol also contains a more distantly related chaperonin known as TRiC (TCP-1-ring complex), TCP-1 complex, cytosolic chaperonin (c-cpn), chromobindin A, or CCT (Chaperonin-containing-TCP-1) that is a member of the group II chaperonins (for review Gonçalves et al. 2007). Although related, both groups of chaperonins are distinct. Group I chaperonins are homo-oligomeric complexes composed of seven-membered rings, whereas group II chaperonins are hetero-oligomeric complexes consisting of eight- or nine-membered rings. Another important difference between the two groups relies in the fact that group I chaperonins act in combination with a co-chaperonin during protein folding. These co-chaperonins are also oligomeric proteins that cap the central cavity of the chaperonin. Group II chaperonins operate without co-chaperonins, but their function is mimicked by helical protrusions formed by an extra sequence localized at the tip of the apical domain (for review Hartl and Hayer-Hartl 2009).

The CCT Complex, Its Interacting Proteins, and Folding Mechanism

CCT exists as a hetero-oligomeric complex of about 900 kDa composed of two back-to-back stacked rings of eight different, though related, gene products that were designated as CCTα to CCTζ (for a review see Gonçalves et al. 2007). T-complex polypeptide-1 (TCP-1) was the first identified subunit of the chaperonin-containing TCP-1 CCT complex. TCP1 was renamed CCTα, whereas the other CCT subunits were designated by CCTβ, CCTε, CCTδ, CCTγ, CCTη, CCTθ, and CCTζ (Cct1 to Cct8 in yeast). The CCTα encoding gene was first cloned from mouse and humans. The mouse gene is highly expressed in the testis and is located in the mouse t-complex region on chromosome 17, which is involved in the transmission ratio distortion of t-complex-carrying mice (Gonçalves et al. 2007).

The CCT complex forms a barrel-shaped cylinder with a diameter of about 150 Å and a height of 160 Å. Within the complex each subunit interacts with one subunit of the opposite ring and it has been shown that CCTα subunits are opposite, or nearly opposite, to each other in opposing rings (for a review see Gonçalves et al. 2007). The arrangement of subunits in the ring moving clockwise is α/1, ε/5, ζ/6, β/2, γ/3, θ/8, δ/4, and η/7. More recently, a new subunit arrangement of CCT was proposed based on crystallography analysis (Kalisman et al. 2013). This unique arrangement in which each subunit occupies a well-defined position seems to be universal throughout eukaryotes (for a review see Gonçalves et al. 2007).

CCT subunits consist of three domains: an equatorial domain containing an ATP-binding site, an apical domain responsible for target protein interaction, and the intermediate domain connecting the other two. The apical domain contains a helical protrusion, which is involved in opening and closing the central cavity of the chaperonin (Llorca et al. 1999) (Figs. 1 and 2).
CCTα, Fig. 1

Several views of the three-dimensional reconstruction of apo-CCT. a and b are side views, with (b) representing a cut along the longitudinal axis of the oligomer, where half of the particle has been removed. c, A top view and d, a side view tilted 35° toward the viewer. The locations of the apical (a), intermediate (i), and equatorial domains (e) are indicated (Figure from Llorca et al. 1999 with permission)

CCTα, Fig. 2

Several views of the three-dimensional reconstruction of ATP-CCT. a and b are side views, with (b) representing a cut along the longitudinal axis of the oligomer. c and f are side views tilted 35° toward the viewer showing the top and bottom ring of the volume in (a), respectively. d and e are top views showing the top and bottom ring of the volume in (a), respectively (Figure from Llorca et al. 1999 with permission)

Phylogenetic analyses revealed that the sequence differences between CCT subunits from different species are located mainly in their apical domains. Although they contain several highly conserved motifs for ATP binding, the overall amino acid sequence identities are only about 30% (for review Gonçalves et al. 2007).

Smaller complexes of CCT-subunit subsets have also been detected in several cell types and were proposed to be intermediates in the assembly of the intact chaperonin (for review Gonçalves et al. 2007). Additionally, CCT subunits have functional differences in vivo which is reflected in the fact that the overexpression of each CCT subunit is not able to rescue mutations in the other CCT subunits, indicating CCT-subunits specificity of function (for a review see Gonçalves et al. 2007).

CCT assists the folding of approximately 5–10% of the cellular proteome being tubulins and actin quantitatively the major substrates (for a review see Lundin et al. 2010). Therefore, the chaperonin is implicated in several processes related to cytoskeleton systems, cell cycle control, nuclear pore complex assembly, chromatin remodeling, and protein degradation. More recently, it was described that CCT is required for the folding of telomerase cofactor TCAB1 which controls the trafficking of telomerase and small Cajal body RNAs involved in telomere maintenance during cell division (Freund et al. 2014). Although most of these proteins do not seem to present a sequence signature which identifies them as CCT interacting proteins, many present WD40 domains, which contain the WD repeat (a weakly conserved sequence motif of ~31 amino acids ending with conserved tryptophan and aspartate residues) and share a β-propeller fold (for a review see Valpuesta et al. 2002). Among the proteins that require CCT for their biogenesis, we find centractin (actin-related protein), septin, von Hippel–Lindau tumor suppressor, histone deacetylases (HDAC3, Set3p, and Hos2p), and cell cycle regulators (Cyclin E, Cdc20p, and Cdc55p) (for reviews see Gonçalves et al. 2007; Dekker et al. 2008). However, not all CCT interacting proteins are chaperonin substrates and are probably involved in the regulation of its activity. For example, proteins such as phosducin-like 1, 2, and 3 (PhLP1–3) bind to CCT in their native forms and were described as modulators of CCT function by competing with CCT substrates or by modulating its ATPase activity (for a review see Willardson and Howlett 2007). Caveolin-1 (a protein that is a major component of caveolae and membrane lipid rafts) also interacts directly with CCT, modulating the folding of actin through the protein filamin (for a review see Gonçalves et al. 2007). Moreover, β-tubulin folding by CCT is regulated by programmed cell death protein 5 (PDCD5) that forms a complex with CCT (Tracy et al. 2014). CCT levels are also regulated through the ubiquitin-proteasome system involving Vaccinia-related kinase 2 (VRK2). By recruiting the E3 ligase COP1, VRK2 downregulates CCT levels, whereas by catalyzing phosphorylation of the deubiquitinating enzyme USP25 causes CCT stabilization (Kim et al. 2015). More recently, it was shown that the protein Misato that is involved in mitotic microtubule assembly is required for CCT complex stability, and its depletion affects both the efficiency of tubulin polymerization and tubulin stability (Palumbo et al. 2015).

The whole CCT complex mediates protein folding, driven by ATP binding and hydrolysis. However, CCT presents an unusual mode of ATP utilization since only four of the eight different subunits (CCTα, CCTβ, CCTδ, and CCTε) bind ATP at physiological concentrations, and ATP-binding to those that present the low-affinity is fully dispensable for CCT function in vivo (Reissmann et al. 2012). It has also been proposed that CCT is partitioned into a substrate binding side that is opposite to the ATP-hydrolyzing side (Kalisman et al. 2013).

Despite the CCT’s prominent role in the folding of a multitude of proteins, its folding mechanisms have been studied mainly for actin and tubulins.

Newly synthesized tubulins and actin are delivered to the CCT complex by prefoldin, a hetero-hexameric complex also referred to as Gim C, which interacts directly with the chaperonin (for a review see Hartl and Hayer-Hartl 2009; Lundin et al. 2010). Tubulin interacts with CCT in a quasi-native conformation through specific interactions with loops in the apical and equatorial domains of CCT, and the substrate seems to be stretched inside the cavity (Muñoz et al. 2011).

It was proposed that actin and tubulin molecules bind to the nucleotide-free (apo-CCT), open conformations of CCT and are thus stabilized in quasi-native conformations that correspond to a high degree of secondary and tertiary structure (Llorca et al. 2001). On binding ATP, the central ring cavity of the ATP-ring expands slightly and is closed by the helical extensions of the apical domains (Llorca et al. 2001). These movements are coupled to the folding movements of actin and tubulin and force the substrate molecules to achieve their quasi-native structures. Llorca et al. (2001) proposed that after ATP binding and hydrolysis the target proteins maintain their interaction with the chaperonin, and the release of the nucleotide leads to the substrate discharge and the regeneration of apo-CCT open conformation (Fig. 3).
CCTα, Fig. 3

Model of the structural changes undergone by the actin and tubulin molecules during the CCT functional cycle. Docking models with the atomic structures of actin and tubulin have been overimposed to the volume of the same proteins complexed with CCT. Quasi-folded actin (1) and tubulin (3) molecules bind to apo-CCT. The N-terminal domains of both cytoskeletal proteins (colored red) bind to CCT with less affinity than the corresponding C-terminal domains. ATP binding induces large movements of the CCT apical domains that seal the cavity. These movements occur sequentially, starting in CCTα, and move in an anticlockwise direction (see yellow arrows in 1 and 3). Following this sequence, the N-terminal domains of both actin and tubulin molecules are the first ones to respond to the rearrangement of the apical domains, resulting in their release and movement toward the C-termini, giving rise to a more native conformation (2 and 4). The C-terminal domains bind to CCT with a higher affinity than the N-terminal domains, and this interaction is maintained after nucleotide binding and hydrolysis. Nucleotide release induces the return to the nucleotide-free, open state and the liberation of the folded substrate. Only one of the possibilities for actin and tubulin binding to CCT is shown, although the other fits equally well with the model proposed (Figure from Llorca et al. 2001 with permission)

CCT: The Cytoskeleton and Cell Cycle Progression

Since the first studies, it was clear that the cytosolic chaperonin CCT was intimately connected with the formation of the cytoskeleton in vivo. For example, in the budding yeast, mutations in the CCTα gene caused both abnormal microtubular structures and disruption of actin microfilaments (for a review see Gonçalves et al. 2007).

Subsequently, TCP-1/CCTα and CCTζ were identified in centrosomes where it may assist microtubule nucleation given that the incubation of these microtubule organizing centers with an antibody against TCP-1/CCTα in vitro prevents microtubule growth (for a review see Brackley and Grantham 2009).

CCTα, CCTγ, CCTζ, and CCTθ subunits associate with microtubules polymerized in vitro behaving as typical microtubule-associated proteins. In addition, TCP-1/CCTα associates with the microtubules of the manchette, a highly specialized microtubule structure of male germ cells (for review Brackley and Grantham 2009). Interestingly, CCT was also identified on the surface of mouse spermatozoa and described to have an indirect role on sperm interaction with the zona pellucida of the oocyte (Dun et al. 2011).

CCT has also been shown to localize in cilia. For example, TCP1/CCTα progressively appears in cilia during the final stages of cilia regeneration in the sea urchin (Gonçalves et al. 2007). In agreement, CCTα, CCTε, CCTδ, and CCTη subunits localize at cilia tips, basal bodies, and other complex microtubule structures in the ciliate protozoa Tetrahymena pyriformis (Seixas et al. 2003). In, T. thermophila, CCTα or CCTδ knockouts caused a loss of cell body microtubules, failure to assemble new cilia, and cell death (Seixas et al. 2010). Additionally, the loss of CCTα subunit activity leads to axoneme shortening and splaying of cilia tips.

Recently, CCT-subunits (CCTα-ε and CCTθ) were shown to form a complex with the chaperonin-like BBS6, BBS10, and BBS12 proteins (vertebrate specific BBS genes) (Seo et al. 2010) required for BBSome assembly. The BBSome is an oligomeric complex of BBS proteins that coats intracellular vesicles and interact with critical proteins, such as small GTPases that are involved in the regulation of the traffic of these vesicles to the cilia membrane (Mourão et al. 2016). In fact, several studies have shown that mutations in BBS proteins underlie the Bardet Biedl Syndrome (BBS), a genetically heterogeneous disorder associated with defects in primary cilia (Seo et al. 2010). More recently it was shown that CCT has a critical role in the biogenesis of vertebrate photoreceptor sensory cilia, probably due to the direct participation of the chaperonin in the posttranslational processing of some BBS proteins with impact on the assembly of the BBSome (Sinha et al. 2014).

The interaction of CCT subunits with membranes was also previously reported. The adrenal medullary form of CCT (chromobindin A) binds efficiently to chromaffin granule membranes (for a review see Gonçalves et al. 2007). Furthermore, in human erythrocytes, CCTα is translocated to the plasma membrane where it binds by a specific association with actin cytoskeleton proteins following a heat shock (for a review see Gonçalves et al. 2007).

CCT has been also implicated in the assembly of the actin cytoskeleton, by acting at filament ends. In fact, the CCT chaperonin interacts with filamentous actin in vitro and decreases the initial rate of actin polymerization (for a review see Brackley and Grantham 2009). Accordingly, the depletion of CCT levels in vivo by CCT-subunit-specific siRNA inhibits cell cycle progression and alterations in microtubule and actin cytoskeleton organization and cell motility (for review Brackley and Grantham 2009).

The fact that CCT subunits do not always co-localize strongly suggest that they might have other functions as free entities or as part of microcomplexes. For example, the CCTα-subunit is more abundant in growing neurites than other CCT-subunits and in yeast the CCTθ subunit appears to play a role in the Ras signaling pathway (for a review see Gonçalves et al. 2007; Brackley and Grantham 2009).

The involvement of specific CCT subunits with actin and microtubule networks seems to indicate that they have, in fact, specific functions outside the whole complex. However, the oligomerization state and the mechanism/s by which CCT-subunits are involved in the assembly and regulation of these dynamic filaments are far from being completely understood and deserve further investigation.

CCT subunits are mainly cytoplasmic; however, CCTα and CCTγ have also been observed to be localized in the nucleus (for a review see Gonçalves et al. 2007). In fact, the 900-kDa CCT complex was isolated from human leukemia K562 cell nucleus (Huang et al. 2012). TCP-1/CCTα was also described to associate with heterochromatin in both somatic and germ cells during mammalian spermiogenesis, and CCT was suggested to assist in the folding of nuclear matrix proteins and proteins involved in DNA remodeling (for a review see Brackley and Grantham 2009). However, it has been suggested that CCTα may have a specific nuclear role because it translocates into the nucleus upon the induction of apoptosis (for a review see Gonçalves et al. 2007). An extensive study of the CCT interactome showed that, besides SET3, and histone deacetylase complex, other enzymes responsible for histone posttranslational modifications interact with CCT which definitively implicates the chaperonin in chromatin remodeling and consequently in gene expression regulation (Dekker et al. 2008).

Numerous evidences suggest an involvement of CCT in cell cycle-regulated events. For example, reducing CCT levels by siRNA assays in mammalian cultured cells leads to cell cycle arrest (for review Brackley and Grantham 2009). Additionally, CCT subunits expression is regulated during cell cycle. The expression of TCP-1/CCTα messenger RNA is strongly upregulated during cell growth especially from the G1/S transition to early S phase (for review Brackley and Grantham 2009). This is supported by observations in the mouse showing that highly proliferative tissues (such as testis, spleen, thymus, and bone marrow) and cultured cells express much higher levels of TCP-1/CCTα and the other CCT subunits than those with low proliferation rates (such as heart, kidney, and lung) (for a review see Gonçalves et al. 2007).

The abundance of CCT varies during the cell cycle which seems to reflect the requirements of the cell for specific cell cycle regulators that are known to interact with it such as cyclin E, cdk-2, cdc20, and Plk1. Besides the alterations in abundance, it was shown that CCT complexes in M-phase-arrested cells have less ability to bind α- and β-tubulin in vivo and for binding and folding β-actin in vitro when compared with the CCT complexes in S phase-arrested cells (for a review see Gonçalves et al. 2007). Thus, the regulation of CCT activity correlates with a fine tuning of the cell cycle by defining the precise moment of folding/assembly of proteins/complexes involved in cell cycle progression.

CCT in Stress Response and Disease

Many molecular chaperones are stress-inducible, making it interesting that the levels of TCP-1/CCTα decrease in S. cerevisiae submitted to hyperthermic stress. Still, the involvement of CCT in stress responses in yeast is illustrated by the fact that CCT1 mutants present decreased resistance to osmotic stress, metal ions, surfactants, and reducing and oxidizing agents (Narayanan et al. 2016). These mutants were also shown to have inherent cell wall defects and decreased ethanol tolerance.

In mammalian cells, the levels of TCP1/CCTα were unaffected when mammalian cells were subjected to heat shock (for a review see Gonçalves et al. 2007). Nevertheless, TCP-1/CCTα, as well as the other CCT subunits, are upregulated in several mammalian cell lines during recovery from chemical stress (sodium arsenite or a proline analogue, l-azetidine-2-carboxylic acid) (for a review see Gonçalves et al. 2007), suggesting that they respond to protein damage and have a function in the recovery of cells from specific stresses.

Taking into account the different observations concerning the response of CCT genes to stress/environmental stimuli, it is plausible that the induction of TCP-1/CCTα by stress conditions may be dependent on the type of stress, cell type, organism, or environmental conditions. Moreover, in some of these studies, the corresponding protein levels were not investigated. The mouse TCP-1/CCTα gene contains in its first intron a heat-shock element that is recognized by the heat-shock transcription factors HSF1 and HSF2, whose overexpression in HeLa cells activates the TCP-1/CCTα gene (for a review see Gonçalves et al. 2007). However, no significant increase in CCT subunits in HeLa cells was detected by western blot analysis after heat treatment at 42–45 °C, whereas Hsp70 protein was induced (for a review see Gonçalves et al. 2007). HSF2 is also known to be important in the tissue-specific and developmental-stage-specific expression of HSPs. This transcription factor is highly expressed in embryos and in testis, and this could indicate that this factor is involved in the regulation of TCP-1/CCTα under non stress conditions.

Many molecular chaperones, e.g., Hsp70, have been extensively implicated in the pathogenesis of a variety of human misfolding diseases.

In the case of CCT, a relationship has been found with neurodegenerative diseases. The Huntington’s disease (HD) is caused by the misfolding and aggregation of proteins with expanded polyglutamine (polyQ) repeats. CCT interacts with polyglutamine-expanded variants of the neuronal huntingtin (Htt) protein and prevents their aggregation and the resulting formation of toxic polyQ fibrils. Depletion of CCT enhances polyglutamine aggregation, whereas its overexpression has the opposite effect, preventing neurotoxicity. Moreover, in mammalian cell models of HD, exogenous administration or overexpression of CCTα reduces aggregation and cytotoxicity (Sontag et al. 2013). In this case, the apical domain of CCTα seems to play a critical role, suggesting that this domain may be used in new therapeutic strategies (Sontag et al. 2013). Interestingly, the CCTα apical domain has been shown to penetrate cell membranes. In this context, this chaperonin may be a key component in the pathway leading to the progression of HD or other pathologies involving misfolded and aggregated proteins, as for example Parkinson disease. Indeed, CCT might play an essential role in the folding of other polyQ expansion proteins like the androgen receptor that is also one of its substrates (Pongtepaditep et al. 2012). Interestingly, it was shown that, in this process, the CCT chaperonin acts synergistically with Hsp70 and Hsp40 on initial oligomer forms of huntingtin promoting the formation of nonpathogenic oligomers (for a review see Hartl and Hayer-Hartl 2009).

The altered expression of some genes encoding CCT subunits was also reported in other pathological processes. For example, TCP-1/CCTα was shown to present altered patterns of expression in the brain in the early stages of developing Down syndrome (for a review see Gonçalves et al. 2007).

Increased levels of TCP-1/CCTα were also reported to be associated with human hepatocellular and colonic carcinoma and in a cisplatin-resistant ovarian cancer cell line (for a review see Lundin et al. 2010). The link between CCTα and cancer is also supported by the observation that the inhibition of the Fibroblast Growth Factor Receptor 2 (FGFR2), that plays an important role in development and tumorigenesis, provokes the decrease of the levels of CCTα in breast cancer cell lines (Guest et al. 2015). Finally, CCTα, with other five CCT-subunits (CCTδ, CCTθ, CCTε, CCTδ, and CCTζA), interacts with the N-terminal cytoplasmic domain of the Lectin-like oxidized low-density lipoprotein receptor (LOX-1) (Bakthavatsalam et al. 2014). This receptor binds oxidized low-density lipoprotein (OxLDL) and has a role in atherosclerosis development. Interestingly interaction of CCTs with LOX-1 is inhibited by OxLDL. The N-terminal domain of the LOX-1 mediates receptor internalization and trafficking which position CCT subunits in the cross-road of cardiovascular diseases.


CCT is an abundant cytosolic chaperonin composed of two hetero-oligomeric stacked rings arranged back to back, with a central cavity that interacts with a large number of distinct cellular proteins as shown by the continuous characterization of the CCT interactome. Among these interacting proteins, some will constitute true substrates, while others will be co-chaperones or regulators. Tubulins and actin are the most prominent cytoskeletal CCT substrates, but by others involved in various cellular processes, such as cell cycle regulation, telomere maintenance, and chromatin remodeling, have also been described. CCT is therefore a key player in the preservation of cellular homeostasis. Many evidences, supported by multiple cellular localizations and by the presence of different oligomeric forms of CCT subunits, have also indicated that CCT subunits may play additional functions outside of the chaperonin complex. For example, it has been proposed that CCT subunits behave as microtubule-associated proteins or regulate actin polymerization. Important is also the fact that some CCT subunits have been found in centrosomes, basal bodies, and cilia axonemes and are essential for the maintenance of the ciliary structure. This places the CCT complex/CCT subunits in multicellular compartments. In conclusion, the misregulation of CCT complex/CCT subunits might be in the basis of a myriad of human diseases based on misfolded and aggregated proteins including neurodegenerative diseases, cancer, and ciliopathies.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sofia Nolasco
    • 1
    • 2
    • 3
    • 4
  • João Gonçalves
    • 5
    • 6
  • Helena Soares
    • 1
    • 3
  1. 1.Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de CiênciasUniversidade de LisboaLisboaPortugal
  2. 2.Instituto Gulbenkian de CiênciaOeirasPortugal
  3. 3.Escola Superior de Tecnologia da Saúde de LisboaLisboaPortugal
  4. 4.Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina VeterináriaUniversidade de LisboaLisboaPortugal
  5. 5.Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de LisboaLisboaPortugal
  6. 6.Lunenfeld-Tanenbaum Research InstituteTorontoCanada