As cell division, directed cell migration, and invasion are major drivers of cancer development and rely on the microtubule and actin filament components of the cytoskeleton, CCT activity is fundamentally linked to cancer. Furthermore, the CCT oligomer also folds proteins connected to cell cycle progression and interacts with several other proteins that are linked to cancer such as tumor-suppressor proteins and regulators of the cytoskeleton, while CCT monomer function can influence cell migration.
Thus, understanding CCT activity is important for many aspects of cancer cell biology and may reveal new ways to target tumor growth and invasion. Structure of the CCT oligomer. Hydrophobic residues are shown in red, others in green. All chaperonin subunits share the same general domain architecture. The equatorial domain contains an ATP-binding site and is connected via a flexible linker region to the apical, substrate-binding domain Fig.
In the case of CCT, the equatorial domains of the eight subunits display high sequence homology, while the apical substrate-binding domains have the most divergent sequences between subunits Kim et al. Thus, CCT has a subunit composition that is unique amongst chaperonins.
The subunit complexity and the need for determining the placement of each subunit within the chaperonin rings have been a major challenge for understanding CCT function. Early conflicting models of the CCT subunit arrangement within the chaperonin rings were based on the composition of CCT micro-complexes of two or more CCT subunits Liou and Willison , or on cryo-electron microscopy Cong et al. The complex nature of the subunit arrangement and size of the CCT oligomer presented a challenge for obtaining high-resolution crystallography data, although the structure of the CCT oligomer bound to actin has been solved at a resolution of 3.
However, a conclusive resolution of the CCT subunit order consistent for both bovine and yeast CCT was achieved using the approach of chemical cross-linking followed by mass spectrometry to identify neighboring subunits Kalisman et al. It is thus necessary to revisit mechanistic studies published prior to these two articles and reassign subunit identities. Here, we will discuss the mechanisms of action of CCT, taking into account both early and more recent studies, as well as giving an overview of CCT activity and the impact of CCT on cellular functions with a focus on cancer cell biology.
Unlike the other chaperonins, CCT consists of eight distinct protein subunits. This creates a unique and complex interaction surface for substrates to bind to, where the geometry of substrate interactions can be determined via the position of CCT subunit-specific binding sites. A major contribution to understanding how CCT interacts with its substrates came from cryo-electron microscopy and single-particle reconstructions of CCT oligomer bound to full-length actin Llorca et al.
This approach revealed that actin and tubulin bind directly to several subunits at once, resulting in both folding substrates spanning the central chaperonin cavity. Both actin and tubulin appear to interact with CCT when partially folded and are described by Llorca et al. Actin interacts with two CCT subunits in a 1. Thus, there is a geometry-specific component to the CCT-substrate interaction that can be determined by substrates interacting with specific CCT subunits. The observations of subunit specificity raise the question of what is the nature of the CCT substrate-binding sites.
Pappenberger et al. Joachimiak et al. They identified a helix and proximal loop on the inside face of the apical domain as being the substrate-binding site with a contribution from Y, which is located in the hinge of the helical protrusion Joachimiak et al. Thus, the nature of the substrate interaction surface of a CCT subunit is not dominated by hydrophobic residues and is thus distinct from the bacterial chaperonin GroEL where interactions with substrates would be expected to be predominantly hydrophobic Chen and Sigler In the case of GroEL, such binding is consistent with GroEL being able to recognize a wide range of unfolded substrate proteins, while in the case of CCT, substrate specificity would be conferred by specific binding sites.
They suggest that binding of substrate to CCT is relatively weak and would thus support multiple binding sites being employed. The range of proteins that use CCT for their folding has been a topic of much debate: does CCT have a broad range of substrates or is it rather restricted? This question is the focus of a recent review article by Willison so will not be dealt with in detail here. However, the complexity of the CCT binding interface and the nature of subunit-substrate interactions, together with CCT not being heat stress-inducible, are consistent with CCT being an essential folding component for a rather discrete subset of folding substrates where actin and tubulin isoforms represent the major CCT substrates.
As actin and tubulin are abundant proteins and are known to be the major co-precipitating proteins in CCT immunoprecipitation experiments Grantham et al. These numbers are based on the work of Thulasiraman et al. As actin and tubulin are very abundant proteins, they alone contribute to a substantial percentage of the radio-labeled proteins bound to CCT Thulasiraman et al. Model of the CCT folding cycle.
Such a wave of ATP hydrolysis could be coupled to the ordered release of the folding substrate. Such a movement could push the actin molecule towards the opposite side of the chaperonin ring Fig. Using the Arrhenius analysis, Gruber et al. This could lead to substrate release where specific points of interaction with substrate can be released sequentially Gruber et al. With regard to substrate binding and processing, a similar scenario appears to be the case for tubulin. Both the electron microscopy of Llorca et al.
As previously suggested Grantham , those substrates that rely upon CCT for folding where specific geometric components of binding are required would be expected to bind to CCT via more than one binding site, thus providing CCT with a mechanical advantage to exert force upon its substrate. Thus, rather than the obligate substrates sharing a common fold that requires interactions with CCT for folding note that the structures of actin and tubulin are not similar , obligate substrates utilize geometrically specific binding conformations in order to receive mechanical input from the nucleotide-driven folding cycle of CCT.
Analysis of the CCT oligomer interactome e. For the obligate substrates, their functions are intrinsically linked to CCT folding activity: if CCT fails to fold such a substrate correctly, then effects from the loss of function of the substrate could occur. Additionally, failure to fold substrate proteins could lead to a toxic gain of function where toxicity could arise from the formation of aggregates and misfolded proteins.
A study on mutations in cardiac actin that are associated with heart disease found that although the actin mutants could be folded by CCT, there was a substantial impact upon their folding efficiency Vang et al. The consequences for cells expressing such mutants are complex. Firstly, the mutant actin proteins could have a direct negative impact on the functional integrity of the actin filaments and secondly, failure to fold efficiently could lead to an accumulation of misfolded proteins. This could potentially lead to a limitation in tubulin dimers and subsequent reductions in microtubule levels that could affect neuronal migration Tian et al.
With both actin and tubulin, it is possible that mutant proteins that fold more slowly could also disrupt the availability for CCT to interact with other folding substrates, potentially leading to other proteins misfolding and thus have a negative impact upon cellular health. When one CCT subunit is targeted for depletion, a reduction in the levels of assembled oligomer occurs, which results in an increase in the non-targeted CCT subunits being present as monomers Brackley and Grantham ; Grantham et al. Therefore, if the targeting of several CCT subunits gives the same results, then it is probable that CCT oligomer function has been affected.
However, if the targeting of one CCT subunit gives a unique outcome, then the possibility of a monomer-related function should be addressed. The reduction of CCT levels in Caenorhabditis elegans affects microtubule-mediated processes during development Lundin et al. Together, these studies show the importance of CCT activity for the folding of actin and tubulin during the development of a whole animal. Saegusa et al. This is consistent with the observations in cultured mammalian cells where upon CCT depletion, there is little change in total actin levels with actin forming aggregate-like structures, but large reductions in tubulin levels are seen Grantham et al.
The complex interplay between CCT and actin and tubulin. Cartoon of a eukaryotic cell depicting the interactions between CCT and the actin- and tubulin-based cytoskeletal systems. Tubulin and actin folding. The CCT oligomer folds newly synthesized tubulin and actin Sternlicht et al.
Regulation of actin transcription. Association with actin filaments. The CCT oligomer can affect the initial rate of actin polymerization but not the final levels of actin filaments in vitro Grantham et al.
Association with microtubules. Some CCT subunits behave as microtubule-associated proteins in vitro Roobol et al. The CCT oligomer can interact with actin filaments, reducing the rate of actin polymerization, but not final levels of actin filaments, in in vitro polymerization assays potentially by acting at the plus end of the actin filaments Grantham et al. An additional way in which CCT may be able to affect actin polymerization is via the actin filament severing and capping protein gelsolin. This suggests that CCT has a role in the regulation of gelsolin activity, possibly acting as a sequestering protein for gelsolin, as CCT is able to inhibit actin filament severing by gelsolin in an in vitro assay Svanstrom and Grantham and adds a further level of complexity to the interplay between CCT and the cytoskeleton.
The serum response factor SRF pathway connects cell surface signaling with actin transcription Sotiropoulos et al. This latter observation is an example of a set of siRNA experiments targeting each of the eight CCT subunits individually revealing a monomeric function. As the loss of assembled CCT oligomer would occur in all eight subunit depletions, such differences in cell shape cannot be attributed to the loss of the CCT oligomer. However, in this case, it was not possible to exclude that the loss of the CCT oligomer was a contributing factor.
The dynactin complex mediates the movement of the dynein motor along microtubules and is thus important for microtubule minus end-directed transport e. Alternatively, the CCT monomers play a more active functional role. The observations of Amit et al. Furthermore, Matalon et al. Thus, it is probable that more CCT subunits will be found to possess individual functions when in their monomeric states.
Chaperonin (Molecular Biology)
How might a monomeric CCT subunit be active? In both these examples, the CCT subunits could be providing a stabilizing interface for misfolded proteins to bind to. However, with regard to the examples of CCT subunits as monomers being involved in the actin and tubulin systems, these functions appeared to occur via various mechanisms.
This could include conferring stability possibly in the case of some CCT subunits being microtubule-associated proteins and increased CCT monomer levels enhancing microtubule regrowth Brackley and Grantham ; Roobol et al. In all of these situations, the ratios of assembled-free CCT subunits will be critical for enabling CCT monomer function and the regulation of CCT assembly may act as a determining switch to allow the cell to balance folding requirements with the modulation assembled cytoskeletal structures and associated functions.
In this section, we will also discuss the relevance of additional CCT interactions for affecting cell cycle progression, tumor-suppressor proteins, and cell migration to give an overview of the extensive role of CCT in cancer cell biology. When a protocol to purify recombinant Hsp60 without a His-tag became available Viitanen et al. Moreover, it became possible to cleave the N-terminal mitochondrial targeting signal MTS present in the eukaryotic Hsp60 and obtain the mature Hsp60 as it occurs inside mitochondria, designated mtHsp The protein was mainly obtained as monomers and heptamers.
Surprisingly, the mammalian mtHsp60 as single toroidal ring was found to be able, in the presence of Mg-ATP and mtHsp10, of facilitating folding of non-native ribulase-P2 carboxylase, forming with it a stable complex. However, in these experiments, a two-ring complex seemed to be an obligatory participant in productive substrate folding Viitanen et al. The formation of single rings was also detected, in the absence of substrate, in studies on human mtHSP60 Nielsen and Cowan, These observations showed that the ability to form single or double rings is confined to the equatorial part of the protein and in particular, as observed for the mutant GroEL SR1 , crucial are the residues R, E, S, and V, that, when mutated into alanine, cause GroEL to form single rings, too.
However, contrary to wild type Hsp60, GroEL SR1 is unable to release client proteins, with the exception of rhodanese. Instead, Hsp60 SR1 , a mutant with mutations at the same positions of mutated residues of GroEL SR1 , and considered to be unable of forming tetradecamers, refolds and releases client proteins. It can, therefore, be inferred that the formation of tetradecamer intermediates, as discussed earlier Viitanen et al.
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Figure 4. Schematics of the substrate-folding cycle of GroEL single rings. According to this proposed mechanism, when the substrate binds to the apical domain of the single ring, the latter rearranges to form a complex with the Hsp10 heptamer. This allows substrate encapsulation and folding with energy from ATP hydrolysis. In contrast to what happens with the full, bullet-shaped complex described in Figure 3 , the interaction between the single Hsp60 ring with the Hsp10 heptamer in the presence of ADP becomes so weak that the ring opens and both, the Hsp10 heptamer and the client-protein are released.
The mutation confers high stability to the open conformation of mtHSP60 so to generate a very stable complex between mtHSP60 and mtHSP10, and with a molecular symmetry that facilitated its crystallization. Thus, the structure of this complex was revealed by X-ray Diffraction Analysis, showing the existence of a football-shaped double-ring oligomer that, although similar to that found for GroEL differs from it in various features Nisemblat et al.
Similarly to GroEL, the N-terminal and C-terminal regions of HSP60 are located in the equatorial domain of the protein that is involved in the inter-ring interface of the oligomeric chaperonin. The rings can both simultaneously bind ATP and one of the seven monomers in each ring is somewhat different from the others so to create an internal asymmetry.
In the football-shape model, the rings independently bind substrate, ATP, and mtHsp10 and, only after that, they join together before encapsulating and refolding the substrate. Therefore, it cannot be excluded that the symmetric, football-shaped intermediate is present also in the chaperoning cycle of the wild type mtHsp In conclusion, it can be hypothesized that different functional mechanisms, involving various types of oligomers, may occur with Hsp60 single rings Nielsen and Cowan, ; Weiss et al.
It is likely that the chaperonin may follow a given pathway depending on substrate type and on micro-environmental conditions such as those occurring under physiological and stress situations. In eukaryotic cells Hsp60 is typically located inside mitochondria, which presumably evolved from prokaryotes via endosymbiosis Gupta, The post-translational import of Hsp60 into mitochondria is, like for other cytosolic proteins that translocate into the organelle, a very intricate process that involves protein translocation complexes such as TOM in the outer membrane and TIM in the inner membrane.
Based on studies on GroEL structure Clare et al. When the Hsp60 N-terminus is analyzed by PONDR VLXT, a neural networks disorder predictor, it appears that in the absence of MTS, residues adjacent to it undergo an order-disorder transition, probably related to the functional role that the chaperonin plays in mitochondria Ricci et al. These studies were stimulated by the increased awareness of the potential roles of Hsp60 in cell compartments other than mitochondria and outside the organelle Soltys and Gupta, ; Cechetto et al.
These locations seem to correspond to specific physiological functions. As an example, in mature insulin secretory vesicles of pancreatic beta-cells, Hsp60, according to its canonical function, could have a role in insulin core condensation necessary for the hormone release Soltys and Gupta, Hsp60 is also involved in assembly of membrane proteins and in the condensation of urate oxidase crystalline core of rat liver peroxisomes. It is especially in pathologic situations such as cancer and autoimmune and inflammatory diseases that HSP60 accumulates in the cytosol, and in extramitochondrial sites Czarnecka et al.
The question still open is how the protein reaches these sites, and, consequentially, which forms of Hsp60 can be found in the various locations. One hypothesis is that cytosolic accumulation of Hsp60 could occur via a mitochondrial export mechanism, which would release Hsp60 devoid of MTS into the cytosol Soltys and Gupta, In this regard, several possibilities can be considered, such as reverse operation of the mitochondrial import channel, or an as yet undefined export pathway, or a movement through lipids, or an export mechanism involving vesicles.
Also, in some cases, Hsp60 can reside and accumulate in the cytosol without being imported into mitochondria and, therefore, this Hsp60 would bear MTS. An example is provided by the LNCaP cells, in which exposure to apoptosis inducers, such as serum starvation or Dox treatment, causes HSP60 accumulation in the absence of mitochondrial release Chandra et al. Moreover, an antibody against the MTS crossreacted with a protein that is present only in the cytoplasm of rat liver cell Itoh et al. It has been demonstrated that in some apoptotic systems mtHsp60 directly interacts with procaspase-3 in the cytosol, enhancing caspase-3 maturation and activation as part of a pro-apoptotic mechanism Samali et al.
In this case, Hsp60 binds procaspase-3 and thereby blocks the apoptotic cascade. Moreover, it was found that from the cytosol, HSP60 was released by tumor cells via exosomes into the extracellular space Merendino et al. Also, elucidation of the oligomeric organization of the chaperonin in all those locations in which it has been detected in pathological situations will no doubt provide new insights into the molecular basis of disease.
In vitro experiments were carried out under conditions approximating as much as possible those occurring in vivo , using HSP60 at a range of concentrations encompassing those believed to occur in vivo : from 10 nM to Even if there are no data from direct measurements on the Hsp60 concentrations in the eukaryotic-cell cytosol or mitochondria, we can assume that the range of concentrations described above should include those found in vivo , in all cell compartments, under physiological, and stress conditions. Our results showed that HSP60 oligomerizes at all the concentration tested, forming both tetradecamers and heptamers with a prevalence of the former and no detectable monomers Vilasi et al.
The results were similar to those described in the preceding lines, although a more marked difference between tetradecamer and heptamer concentrations was found. In this case, the HSPHis6-tag purification via Affinity Column Chromatography yielded a protein unable to oligomerize and occurring exclusively as monomers. Instead, the protein without His6-tag, studied by EM, Native Gel Electrophoresis, and Light Scattering appeared as tetradecamers with a minor part of heptamers. It has not yet been established what form, monomer, or single or double ring occurs in the cytosol.
We hypothesize that this form does not disassemble before entering, as monomer, into mitochondria. It is likely that cytosolic chaperones, such as Hsp70 and Hsp90, bind the Hsp60 precursor and usher it into mitochondria thus preventing oligomerization in the cytosol. However, we can only say at this time, that in the case of HSP60 accumulation resulting from the failure of the chaperonin precursor to enter into mitochondria, the protein has the ability to form the toroidal structure, probably as necessary to perform its functions in those specific conditions.
Figure 5. The pattern reveals that the protein exists in two oligomeric forms independently of the concentration. Adapted from Vilasi et al. It is worth noting that mature HSP60 produced without His6-tag occurs predominantly as single rings Nielsen and Cowan, ; Parnas et al. Structural differences between the two HSP60 forms can also be inferred from the studies on the chemical stability of the two proteins, Figure 6 Ricci et al.
In order to corroborate this suggestion, further studies are needed to directly compare the two proteins, possibly purified under the same conditions, also in relation to their different activity. Figure 6. Details on data analysis are reported in Ricci et al. The functions of Hsp60 are closely related to its structure and, therefore, any changes in composition and conformation due to mutations or aberrant post translational modification PTM may cause a chaperonopathy. Most likely, some PTMs occur during the synthesis of the Hsp60 peptide at or near the ribosome and also later, but before the folding process necessary to yield a mature, functional Hsp60 monomer, ready to display its functions alone or as part of a heptamer or tetradecamer.
Several lines of research are currently underway aimed to: a clarify how PTM change Hsp60 properties and functions and, thereby, its physiological roles; and b determine its etiopathogenic activity in chaperonopathies. For instance, a recent study examined HSP60 hyperacetylation during anticancer-drug treatment in human osteosarcoma cells Gorska et al. The results lead to the working hypothesis that the post-translational hyperacetylation of HSP60 associated with administration of geldanamycin, contributes to the death of cancer cells.
More recently, it was reported that HSP60 hyperacetylation and ubiquitination are associated with the response of cancer cells to administration of the anticancer-drug doxorubicin Marino Gammazza et al. Hyperacetylated HSP60 would be directed via ubiquitination to the proteasome system, which would cause a decrease or loss of HSP60 functions, leading to the re-instauration of cellular senescence in cancer cells followed by tumor-cell growth arrest, Figure 7.
Chaperone-assisted protein folding I: Chaperonins
Also, in line with these data is the finding that HSP60 modifications have an impact on its trafficking, favoring its secretion into the extracellular space Campanella et al. Figure 7. Proposed anti-cancer mechanism of action of doxorubicin involving human HSP In the absence of doxorubicin, HSP60 shown as Hsp60 to encompass not only the human chaperonin but also any other ortholog from animal experimental models can form complexes with p53 thereby removing free p53 and, thus, there is no interaction between it and p21, which results in the abolition of senescence; the tumor cell is immortal.
In this situation HSP60 has an essential pro-tumor effect. Doxorubicin cancels this effect, an action that is associated with HSP60 acetylation. It was found that the histone deacetylase inhibitor, suberoylanilide hydroxamic acid SAHA is cytotoxic for tumor cells, an effect associated with changes in the levels of concentration and nitration of HSP60, Figure 8 Campanella et al. The nitrated protein could be exported via extracellular vesicles, such as exosomes Campanella et al. Since exosomes are extracellular vehicles that transport factors associated with cancer progression and factors that can modulate the immune response, the presence of HSP60 in them suggests involvement of this chaperonin in inflammation, immune system modulation, and regulation of tumor microenvironment and growth.
Figure 8. In the absence of SAHA, the levels and quality of HSP60 shown as Hsp60 to encompass not only the human chaperonin but also any other ortholog from animal experimental models and mitochondria are those required by the tumor cell to grow and proliferate.
HSP60 levels decrease, the protein is nitrated, i. In summary, our most recent work has provided new insights, supporting the idea that post-translational modification of HSP60 are associated with key changes inside and outside cells. For instance i acetylation is accompanied by a decrease of HSP60 levels and functions such as interaction with p53, and re-instauration of senescence in tumor cells; ii acetylation and ubiquitination most likely leads to HSP60 degradation in the proteasome; and iii HSP60 nitration affects its trafficking, favoring its translocation into exosomes and subsequent secretion into the circulation, a situation that allows HSP60 to reach target cells, near or far, and thus exercise, for instance, a regulatory action on the immune system.
Working hypotheses for studying the effect of PTM on Hsp60 in tumor cells treated with anti-cancer drugs are depicted in Figures 7 , 8.
Hsp60 monomers in solution tend to associate into oligomers and form heptameric rings, and double rings, i. The latter seem to be the preferred functional complex.
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However, single rings may also have functions in vivo , without the need for tetradecamer intermediates, under normal and pathologcal conditions. This point deserves more research because single rings may participate in cellular mechanisms which, if elucidated, will enhance our understanding of molecular chaperones and their roles in health and disease. Monomers as such, despite their tendency to oligomerize when in solution, may also play important roles in health and disease.
We know that Hsp60 occurs in mitochondria, cytosol, other organelles, the plasma cell membrane, the intercellular space, and in circulation free or attached to corpuscular bodies such as red and white cells, or in exosomes. It is likely that at least in some of these locations Hsp60 is present as monomers, the functions of which deserve active investigation, as much as heptamers and tetradecamers do.
Other structural details of Hsp60 in health and disease that deserve close scrutiny are PTM. These molecular modifications may be crucial for determining: i with which of the various possible interactive partners Hsp60 will interact; ii the locale in which it will reside and function; iii ; which of the several physiological roles the Hsp60 molecule is able to play will in fact be played; and iv whether the chaperonin will be cytoprotective or pathogenic.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Bie, A.
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- 2. Function.
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Table of Contents
Georgopoulos, C. Identification of a host protein necessary for bacteriophage morphogenesis the groE gene product. Goloubinoff, P. Reconstitution of active dimeric ribulose bisphosphate carboxylase from an unfolded state depends on two chaperonin proteins and Mg-ATP. Gorska, M. Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 hsp Gupta, R. Evolution of the chaperonin families Hsp60, Hsp10 and Tcp-1 of proteins and the origin of eukaryotic cells. Mitochondrial matrix localization of a protein altered in mutants resistant to the microtubule inhibitor podophyllotoxin.
Cell Biol. Hansen, J. Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 separated by a bidirectional promoter. Hemmingsen, S. Homologous plant and bacterial proteins chaperone oligomeric protein assembly. Hohn, T. Isolation and characterization of the host protein groE involved in bacteriophage lambda assembly. Horwich, A. Protein folding in the cell: an inside story. Two families of chaperonin: physiology and mechanism.
Cell Dev. Hutchinson, E. Identification and electron microscopic analysis of a chaperonin oligomer from Neurospora crassa. EMBO J. Illingworth, M. Ishii, N. FEBS Lett. Itoh, H. Mammalian Hsp60 is quickly sorted into mitochondria under conditions of dehydration. Jindal, S. Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the kilodalton mycobacterial antigen. Kalderon, B. Cytosolic Hsp60 can modulate proteasome activity in yeast. Kim, H. Heat shock protein 60 modified with O-linked N-acetylglucosamine is involved in pancreatic beta-cell death under hyperglycemic conditions.
Related The Chaperonins (Cell Biology)
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