Analyses of proteomes from a large number of organisms throughout the domains of life highlight the key role played by multiprotein complexes for the implementation of cellular function. While the occurrence of multiprotein assemblies is ubiquitous, the understanding of pathways that dictate the formation of quaternary structure remains enigmatic. Interestingly, there are now well-established examples of protein complexes that are assembled co-translationally in both prokaryotes and eukaryotes, and indications are that the phenomenon is widespread in cells. Here, we review complex assembly with an emphasis on co-translational pathways, which involve interactions of nascent chains with other nascent or mature partner proteins, respectively. In prokaryotes, such interactions are promoted by the polycistronic arrangement of mRNA and the associated co-translation of functionally related cell constituents in order to enhance otherwise diffusion-dependent processes. Beyond merely stochastic events, however, co-translational complex formation may be sensitive to subunit availability and allow for overall regulation of the assembly process. We speculate how co-translational pathways may constitute integral components of quality control systems to ensure the correct and complete formation of hundreds of heterogeneous assemblies in a single cell. Coupling of folding of intrinsically disordered domains with co-translational interaction of binding partners may furthermore enhance the efficiency and fidelity with which correct conformation is attained. Co-translational complex formation may constitute a fundamental pathway of cellular organization, with profound importance for health and disease.

How do protein complexes form?

Proteins rarely act in isolation but operate as components of so-called protein ‘machines’ [1]. A comprehensive understanding of the mechanisms that govern the formation of protein assemblies is, therefore, paramount for the understanding of cellular functions. A cell harbors hundreds of different protein machines that vary immensely with respect to their complexity. Some proteins simply require the association of multiple copies of the same subunit, like the homo-tetrameric GAPDH enzyme, while others require many subunits like, e.g. the 26S proteasome with ∼31 different polypeptides [2] and the ribosome that contains four RNAs in addition to some 85 protein molecules [3]. To facilitate the efficient formation of a cell's repertoire of protein machines, the availability of all components must be warranted, the formation of correct interactions must be promoted, incorrect interactions must be resolved and last but not least, the complete association of all necessary components must be established. Currently, it remains largely unknown how those requirements are met, suggesting that essential layers of cellular regulation remain to be uncovered.

The dynamic nature of assembly processes and the short lifetime of assembly intermediates are major obstacles that hamper biochemical and cell biological analyses. Because of this, protein complex formation often is being studied in vitro using purified subunits. The outcomes of such approaches likely influenced models for complex formation in vivo, which typically assume individually translated subunits and stochastic assembly processes involving protein diffusion, i.e. post-translational assembly [4,5]. The intrinsic complexity of many protein assemblies suggests, however, that diffusion-dependent models are too simplistic to account for efficient complex formation. This is because the crowded environment inside cells is likely to give rise to nonspecific and potentially problematic interactions [6]. Moreover, proteins are being synthesized in a single dividing yeast cell by some 1.7 × 105 ribosomes that are engaged simultaneously on 6 × 104 mRNA transcripts [7]. Thus, there is a continuous stream of nascent chains emerging from ribosomes that are available for interaction, and the formation of such interactions will be promoted by the relatively slow rate of protein synthesis (∼15–20 amino acid per second).

A common theme for complex formation is the existence of highly orchestrated pathways, which prescribe an obligatory sequence of subunit association [8,9]. The outcomes of these assembly processes are under continuous surveillance by efficient quality control systems. This includes, for example, process-specific molecular chaperones that prevent incorrect associations of ribosomal [10] and proteasomal subunits [1113] and the targeted removal of unincorporated or misfolded subunits [8,14]. The availability of complex components is warranted through the co-regulation of protein synthesis rates of interaction partners, which has been adapted to accommodate subunit stoichiometry [15,16]. While steady progress is being made in advancing the understanding of formation for isolated complexes, the problem remains unresolved for the bulk of cellular protein. In this review, we discuss the specific advantages that co-translational protein interactions offer to promote and control the formation of protein complexes.

Co-translational complex formation: an emerging concept

Given the large diversity of protein assemblies, it seems likely that the mechanisms of complex formation are manifold and rely on protein interactions that are established both in a post- and co-translational manner (Figure 1). A co-translational mode is excluded for pathways like ribosome synthesis, which is coupled to RNA polymerase I transcription in the nucleolus [17] or in the case of organellar complexes where interaction partners are synthesized in separate compartments [18]. Co-translational assembly of homomeric complexes was suggested as early as 1963 with β-galactosidase (Figure 1A; [19,20]), and in the 1980s, for complexes in cell matrix systems such as the myosin heavy chain [21]. There has since been a steady increase in the number of reports describing complexes that are formed co-translationally (Table 1). The co-translational assembly of homomers in the cytoplasm seems not surprising, given the high concentration of nascent proteins [2224]. Also, homomer assembly is greatly simplified, in that it does not require a specific order of subunit association. Nevertheless, co-translational assembly of heteromers has been demonstrated or inferred in many reports for complexes that assemble in the cytosol [2527]. Moreover, co-translational interactions of nascent peptides have been observed for membrane-associated [2830] and secreted proteins [31,32]. At the endoplasmic reticulum (ER), the translocon facilitates the insertion of transmembrane proteins into the phospholipid bilayer or the translocation of soluble proteins into the ER lumen, respectively [33]. Thus, co-translational interactions at the ER require spatial proximity of native ribosome–translocon complexes, sufficient length of nascent peptides to span the translocon space and the presence of amino-terminal interaction domains as was suggested for tenascin hexabrachion formation [31].

Pathways for intracellular assembly of protein complexes.

Figure 1.
Pathways for intracellular assembly of protein complexes.

(A) In prokaryotes, structural genes present on polycistronic operons are co-translated on polysomes resulting in high local concentrations of nascent protein. This facilitates efficient assembly of complexes by increasing the probability associated proteins will interact, either post-translationally (e.g. β-galactosidase dimers and tetramers) or co-translationally as seen for LuxA/B. (B) Fused genes and multienzyme proteins can facilitate complexes with defined stoichiometry. (C) In eukaryotes, transcripts encoding individual proteins can be co-localized within the cytoplasm by mRNA zip codes (Arp2/3, hERG and SAGA). Complexes can assemble from mature subunits post-translationally, or co-translationally on hub proteins as these are being synthesized (Set1C).

Figure 1.
Pathways for intracellular assembly of protein complexes.

(A) In prokaryotes, structural genes present on polycistronic operons are co-translated on polysomes resulting in high local concentrations of nascent protein. This facilitates efficient assembly of complexes by increasing the probability associated proteins will interact, either post-translationally (e.g. β-galactosidase dimers and tetramers) or co-translationally as seen for LuxA/B. (B) Fused genes and multienzyme proteins can facilitate complexes with defined stoichiometry. (C) In eukaryotes, transcripts encoding individual proteins can be co-localized within the cytoplasm by mRNA zip codes (Arp2/3, hERG and SAGA). Complexes can assemble from mature subunits post-translationally, or co-translationally on hub proteins as these are being synthesized (Set1C).

Table 1
Protein complexes for which co-translational assembly has been suggested
Name Type Organism Year, Reference 
β-Galactosidase Homomer Prokaryote 1963, [19,20
Immunoglobulin Heteromer Eukaryote 1979, [32
Myosin heavy chain Homomer Eukaryote 1987, [21
Tenascin intermediate filament Homomer Eukaryote 1995, [31
Reovirus cell attachment protein σ1 Homomer Eukaryote virus 1996, [83
D1 protein of photosystem II Heteromer Eukaryote 1999, [28
NF-κB1 p50 subunit Homomer Eukaryote 2000, [22
Voltage-gated K+ channel Heteromer Eukaryote 2001, [29
p53 Homomer Eukaryote 2002, [23
IgE high-affinity receptor Heteromer Eukaryote 2005, [30
Periferin Homomer Eukaryote 2006, [24
Set1C Heteromer Eukaryote 2009, [25
Various S. pombe proteins  Eukaryote 2011, [26
Luciferase Heteromer Prokaryote 2015, [34
hERG ion channel Heteromer Eukaryote 2016, [46
SAGA histone acetyltransferase Heteromer Eukaryote 2017, [27
Name Type Organism Year, Reference 
β-Galactosidase Homomer Prokaryote 1963, [19,20
Immunoglobulin Heteromer Eukaryote 1979, [32
Myosin heavy chain Homomer Eukaryote 1987, [21
Tenascin intermediate filament Homomer Eukaryote 1995, [31
Reovirus cell attachment protein σ1 Homomer Eukaryote virus 1996, [83
D1 protein of photosystem II Heteromer Eukaryote 1999, [28
NF-κB1 p50 subunit Homomer Eukaryote 2000, [22
Voltage-gated K+ channel Heteromer Eukaryote 2001, [29
p53 Homomer Eukaryote 2002, [23
IgE high-affinity receptor Heteromer Eukaryote 2005, [30
Periferin Homomer Eukaryote 2006, [24
Set1C Heteromer Eukaryote 2009, [25
Various S. pombe proteins  Eukaryote 2011, [26
Luciferase Heteromer Prokaryote 2015, [34
hERG ion channel Heteromer Eukaryote 2016, [46
SAGA histone acetyltransferase Heteromer Eukaryote 2017, [27

Recently, the first example of co-translational heteromer assembly in prokaryotes was elegantly demonstrated using recombinant bacterial luciferase expressed in Escherichia coli [34] (Figure 1A). Previous work found that LuxB folds co-translationally, but suggested that the formation of active luciferase heterodimer occurs only after LuxB is released from the ribosome [35]). Shieh et al. constructed operons that expressed the two luciferase subunits (luxA and luxB) tagged with two different fluorescent proteins. They then went on to demonstrate that the tandem arrangement on the operon transcript promoted the assembly of heterodimers near the site of protein synthesis. Furthermore, ribosomes in the process of synthesizing LuxB co-immunopurified with LuxA, establishing that dimerization occurred indeed co-translationally. Importantly, operon association of the structural genes not only promoted cis-assembly through localized subunit translation, but also positively affected the functional outcome of complex formation. Trans-assembly, with equivalent levels of LuxA and LuxB expression but from separate mRNA transcripts, yielded only 60% of the luciferase activity. The discrepancy is not due to subunit aggregation in the later arrangement, but the greater efficiency of cis-assembly giving higher activity [34]. Moreover, the ribosome-associated trigger factor appears to control the timing of LuxB–LuxA binding during the translation and folding process. Differential effects of trigger factor on assembly were observed depending on the order of subunit synthesis, suggesting that the chaperone prevents premature protein interactions and allows for the optimization of subunit assembly. Together, these results reveal that polycistronic organization of gene expression in operons allows prokaryotes to integrate all aspects of heteromer synthesis: co-ordinated regulation of gene expression, subunit stoichiometry and promotion of co-translational interactions (Figure 1A). Interestingly, it was recently suggested that stoichiometry and tuning of individual subunit levels are controlled predominantly at the level of translation, perhaps by differential initiation although the precise mechanisms are not known [15]. Since the majority of multiprotein complexes in prokaryotes are encoded in operons, it seems likely that many protein interactions will be promoted via polycistronic expression suggestive of a fundamental importance for co-translational complex formation and its regulation.

Promoting co-translation and co-translational interactions: from polycistrons to co-localization of mRNA

One key objective for polycistronic gene arrangements appears to be the formation of high local concentrations of nascent peptide chains. While operons do not occur ubiquitously in biology, rare examples of polycistronic organization also exist in eukaryotes like, e.g. in Caenorhabditis elegans, suggesting that this genomic organization harbors inherent advantages for complex assembly. Eukaryotic operons are, however, uncommon, whereas protein complexes tend to be larger and more elaborate compared with prokaryotes. How then do eukaryotes compensate for the absence of operons? One way to achieve the co-ordinated and co-localized translation that results from the single encoding operon mRNA is through fusion of multiple subunits within a single gene ([8]; Figure 1B). Consequently, multienzyme proteins frequently have continuous open reading frames where individual enzymic functions are found on distinct domains of a single polypeptide chain (reviewed in ref. [36]). However, this arrangement strictly dictates subunit stoichiometry and imposes structural constraints on the overall folding of the fusion protein; the orientation and linkage of domains relates directly to the length of the linker polypeptide between the C-terminus of one domain and the N-terminus of the next. Such constraints may limit the number of possible fusion proteins that are able to provide functionality (e.g. allosteric control) as seen with complexes containing quaternary structure [8].

A more accommodating mechanism to deliver some of the advantages conveyed by operons would be the co-localization of mRNAs in the eukaryotic cytosol (Figure 1C). It has been suggested that ensuring a locally high concentration of subunits may enhance the co-translational interaction of nascent peptides as they emerge from ribosomes [24]. Conceptually, this could be achieved via targeted and asymmetric mRNA localization that concentrates the translation of functionally related gene products. Asymmetric cellular distribution of mRNA has been associated with diverse processes in eukaryotes, such as budding of yeast cells [37], during the establishment of metazoan body axes [38], and during cell migration and neurite outgrowth [39,40]. Intriguingly, the co-localization of mRNAs for whole complexes and, therefore, the encoded subunit proteins have been demonstrated for the seven-subunit Arp2/3 complex along the protrusions of human fibroblasts [41]. While it remains to be shown whether the Arp2/3 complex subunits indeed engage in co-translational interactions, the co-localization of mRNAs indicates that efficient formation of protein interactions does not simply rely on random diffusion of subunits within the cell. mRNA co-localization may involve RNA zip codes, which resemble structurally diverse regions in 3′-UTRs capable of directing and anchoring transcripts to specific cytoplasmic domains [42]. The activity of 3′-UTRs is being modulated by mRNA-binding proteins [43] that are likely to contribute to the interpretation of RNA zip codes. The movement of mRNA can involve simple diffusion, but is usually driven by motor proteins associated with the cytoskeleton [44,45]. Consistent with this idea, the co-purification of the mRNAs encoding the heteromeric ion channel hERG 1a and 1b subunits was achieved with antibodies directed against the nascent 1a N-terminus [46]. Interestingly, the interaction of the two transcripts occurred independently of the encoded proteins prompting Liu et al. [46] to suggest the intriguing possibility that RNA-binding proteins bound to RNA zip code establish a ‘microtranslatome’ that generates physical proximity of nascent proteins to promote the efficient formation of the heteromeric complex. Tethering of mRNAs is an efficient mechanism to enhance the concentration of nascent polypeptides. In yeast, a tethering function has been suggested for the Ccr4–Not complex in the co-translational assembly of Ada2 and Spt20 components of the SAGA histone acetyltransferase [27]. Importantly, recent advances including single mRNA resolution FISH techniques [47] and the real-time observation of single mRNA in life cells [48] make it now possible to systematically probe the co-localization of mRNAs that contribute to the same protein complex, promising substantial progress in this important field in the near future.

Surveillance of complex formation through kinetic competition between assembly and degradation?

The correct assembly of heteromeric complexes requires control by the cell of at least three global parameters: (i) spatial, (ii) temporal coordination of subunit synthesis and (iii) their accumulation to levels appropriate to the stoichiometry and kinetics of heteromer formation. Beyond these broad requirements, other variables must be controlled and optimized, such as the ordering of subunit binding, prevention of misfolding or inappropriate/nonspecific interactions. Although there may be numerous means by which the processes and constraints may be addressed, co-translational control of complex formation seems, at least potentially, to make a powerful contribution to achieving the required level of organization (Figure 2).

Hypothetical layers of regulation and quality control in the formation of protein complexes.

Figure 2.
Hypothetical layers of regulation and quality control in the formation of protein complexes.

Solid color of core subunits indicates nascent proteins, where the no-fill symbol indicates a mature protein. Round symbols indicate free subunits, whereas square symbols indicate assembled subunits. Core subunit translation in the presence of a pool of already synthesized attachment subunits leads to complex formation in a dynamic, co-translational fashion. In the absence of key subunits, surveillance of folding and exposure of the core may lead to degradation of the nascent protein (i). This prevents accumulation of incomplete complexes, as well as the depletion of pools of attachment subunits. Stable sub-complexes, in contrast, may subsequently bind further subunits in a (iv) co-translational or (v) post-translational manner. Errors in protein–protein interaction would also lead to degradation of the nascent core and release individual subunits to the cellular pool (iv). The expression of complexes may be independently sensitive to a limiting concentration of individual subunits, enabling a rapid response to changes. Where subunits are common to more than one complex (vi), switching of simultaneous or alternative expression would depend on whether complex formation is limited by shared or independent subunits, respectively.

Figure 2.
Hypothetical layers of regulation and quality control in the formation of protein complexes.

Solid color of core subunits indicates nascent proteins, where the no-fill symbol indicates a mature protein. Round symbols indicate free subunits, whereas square symbols indicate assembled subunits. Core subunit translation in the presence of a pool of already synthesized attachment subunits leads to complex formation in a dynamic, co-translational fashion. In the absence of key subunits, surveillance of folding and exposure of the core may lead to degradation of the nascent protein (i). This prevents accumulation of incomplete complexes, as well as the depletion of pools of attachment subunits. Stable sub-complexes, in contrast, may subsequently bind further subunits in a (iv) co-translational or (v) post-translational manner. Errors in protein–protein interaction would also lead to degradation of the nascent core and release individual subunits to the cellular pool (iv). The expression of complexes may be independently sensitive to a limiting concentration of individual subunits, enabling a rapid response to changes. Where subunits are common to more than one complex (vi), switching of simultaneous or alternative expression would depend on whether complex formation is limited by shared or independent subunits, respectively.

The Set1 complex (Set1C) is a histone H3 lysine four methyltransferase. The enzyme consists of seven subunits, which bind to the catalytic Set1 subunit that acts as an assembly platform [49,50]. It was found that the assembly of a Set1C sub-complex is initiated during polysomal synthesis of Set1, enabling isolation of other subunits along with nascent Set1 protein and its mRNA ([25]; Figure 1C). Interestingly, only three of the seven subunits co-purified with Set1 polysomes, which is consistent with the proposal that ordered assembly of complexes proceeds via favored intermediate sub-complexes [51].

The observation by Halbach et al. is, however, more than just a reflection of a sub-complex assembly process. We showed that the accumulation of Set1 protein was dependent on the presence of other subunits, not only from the co-purifying sub-complex, but also subunits confined to mature Set1C. This indicates that the cellular protein degradation machinery actively targeted nascent Set1 under conditions when key interaction partners were not available (Figure 2, pathway i). Consistent with this idea, nascent proteomes have been found to be targeted by co-translational ubiquitylation in yeast [52] and human cells [53] and co-translational targeting by the proteasome has been demonstrated to efficiently suppress the accumulation of unstable protein [54]. Interestingly, quality control at the ribosome has been suggested to involve ‘kinetic competition’ between co-translational protein degradation and co-translational protein folding [54]. In analogy to this concept, we speculated that kinetic competition between co-translational protein interactions and co-translational degradation may constitute surveillance of Set1C assembly [25]. Notably, the concept of kinetic competition also extends to RNA synthesis, where nascent RNA is subjected to competing reactions involved in maturation and degradation, respectively [55]. This major quality control function in the eukaryotic cell thus ensures that RNA is produced accurately. It will be interesting to see whether kinetic competition will apply more broadly as quality control mechanism for the formation of protein complexes.

A role for intrinsically disordered domains in the co-translational assembly of complexes?

In parallel with the discovery of co-translational complex formation has been the realization that a large proportion of proteins have regions with intrinsic disorder [5658]. The picture to emerge is that protein disorder can play a crucial role in protein function, particularly through its involvement in protein–protein interactions. Protein folding and protein binding are regularly coupled processes; the mechanisms by which they occur entail interactions between unstructured and already structured regions that induce folding and transition to complementary conformations in binding partners [59,60]. The involvement of disorder in many protein–protein interactions has led to the recognition that intrinsically disordered proteins promote the formation of protein complexes in which they are very commonly present [61], for recent reviews, see [62,63]. This might have direct implications for co-translational complex assembly. For instance, the lack of a native fold that characterizes disordered segments of polypeptide means that they have the potential to recruit intended targets as soon as they emerge from the ribosomal exit tunnel, or otherwise become the targets of co-translational degradation [64].

The hypothesized recruitment of already formed binding partners co-translationally by disordered or partially folded regions of nascent peptide would have several potential benefits. Chaperone-like assistance in folding is one such possibility [59,60]. However, the presence of disorder, whether intrinsic or in regions of unresolved folding due to the absence of binding partners, can also render proteins susceptible to degradation, suggesting involvement of such regions in the ubiquitin–proteasome system for cellular control [65]. Furthermore, the ‘nanny’ model proposes that intrinsically disordered regions may be masked by interacting proteins without promoting complete protein folding [66]. Such persistence of structural ambiguity in established protein–protein interactions has been referred to as ‘fuzziness’ [64]. Fuzzy binding by a nanny protein can act to protect the disordered region from default degradation thereby enabling the maturation of the functional complex (reviewed in ref. [67]). Interestingly, intrinsically disordered proteins commonly act as core subunits in protein complexes onto which attachment subunits assemble [68]. A corollary to this is that the ordering of subunit binding in the growing complex could be facilitated by the order in which regions of core peptide are synthesized on the ribosome, and induced to fold as partners dock with the polysome [63]. In turn, such a process provides quality control checkpoints in assembly, as a nascent protein that fails to fold or otherwise become protected would rapidly be targeted for degradation. This would facilitate a means of spatial and temporal sensing whether all critical subunits were available. Although this process might appear ‘wasteful’, it would achieve tight regulation of complex expression, with respect to both quality and accumulation (Figure 2). Consistent with this, recent studies have found that unassembled subunits are targeted for degradation by co-translational N-terminal acetylation [69] and assembly-control of protein degradation now appears to be a determinant of complex quality and subunit stoichiometry [15].

The existence of co-translational assembly, therefore, has implications for complex expression regulation, as well as quality control. Where there are a large number of different attachment subunits, final complex expression would be sensitive to their individual cellular levels, alternatively minimizing or maximizing the number of subunits controlling the assembly process. The low abundance of any particular subunit would not lead to the accumulation of nonfunctional and incomplete complexes that would, as a result, lock up other associated subunits, thus preventing what has been dubbed ‘combinatorial inhibition’ [7072]. In this way, co-translational control would enable a fine balance between subunit availability and complex formation, including ‘moonshining’ proteins that are members of multiple complexes (Figure 2, pathway vi). Translation-level regulation of complex assembly would thus provide a means of cross-talk between pathways in which they operate, and the rapid redirection or metabolic switching of cellular processes [73,74]. It would constitute a feedback mechanism to control protein complex expression via their individual component subunits. An example of such a complex cross-talking subunit is Swd2, which is required for the stable accumulation of Set1C [75,76]. Swd2 is also a member of the APT complex, which is involved in processing the 3′-terminus of mRNAs and snoRNAs [77]. Soares and Buratowski [78] have analyzed the effects of modulating Swd2 levels and proposed a model of antagonistic competition between Set1C and APT during transcription, mediated by their common subunit. The assembly pathway of Set1C has not been fully elucidated, so the involvement of co-translational assembly in the regulation of the process, and how this may affect the interplay between Set1C and APT, will require further investigation.

The nonlinear sensitivity of assembly systems to dosage effects from individual components has been explored theoretically [79]. Heteromeric complexes can be viewed as a network of constituent subunits. Fluctuations in the concentrations of subunits can, for example, result from overexpression or knockout mutation in one gene allele. For networks to be robust to such fluctuations, there needs to exist compensatory mechanisms [80]. The proposed co-translational control of complex assembly outlined here would appear to supply such a palliative mechanism, and is consistent with the preferential protein degradation model of Veitia and co-workers [80]. Furthermore, co-translational control would enable cells to exploit subunit dosage effects as a means of regulating complex expression. The observation that co-ordinated subunit expression for many essential complexes involves post-transcriptional regulation is also consistent with this proposal [74]. Indeed, rapid regulatory responses in the abundance of a product of a pathway are best facilitated by control at the last possible production step [74]. In the case of a complex, this would suggest its assembly.

Conclusion

In this review, we discuss the characteristics as well as the known and proposed benefits of co-translational complex assembly. Currently, the critical features that necessitate co-translational interactions inside the cell remain poorly defined. We speculate that co-translational assembly will be most important for complexes that carry a high propensity for incorrect or incomplete assembly and maturation. Reasons for this could be low-level expression, a large number and variety of assembled subunits, or structural constraints like induced fit and folding sequences. How widespread is co-translational assembly? A systematic approach based on mRNA co-purification in Schizosaccharomyces pombe indicated that up to 38% of analyzed examples involved co-translational interactions, suggesting this to represent a major mode of complex formation [26]. Further characterization of co-translational examples in different organisms will be required to generate a coherent overview of the necessity for this assembly mode and to derive underlying commonalities. Importantly, a major future challenge will be to demonstrate biological roles for co-transcriptional assembly. The luxA–luxB example [34] illustrates that co-translation indeed promotes enhanced functionality of the assembled protein machine, but such biological relevance remains to be demonstrated for most other examples. Protein complexes are involved in all aspects of cell metabolism and the maintenance of structure, and in higher eukaryotes, they conduct essential functions such as cell signaling and immune surveillance (for reviews, see refs [81,82]). As such, macromolecular complex assembly and expression regulation have enormous implications for our understanding of disease etiology. It seems likely that as yet poorly understood, regulatory systems involve the co-translational control of complex formation and that the elucidation of these systems will strongly enhance our understanding of cellular function.

Abbreviations

     
  • ER

    endoplasmic reticulum

  •  
  • Set1C

    Set1 complex

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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