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Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation
Cell Communication and Signaling volume 13, Article number: 45 (2015)
A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.
The life of a gene product, from transcription to degradation, is controlled by a series of regulatory decisions. How does the cell decide when to make a transcript? Does a transcript get translated, stored, decayed or transported to a specific subcellular location? After translation, where is a protein localised, and what complexes should it join? Ultimately, when is a protein degraded? The outcome of this decision-making process is cell state dependent and, consequently, requires the integration of vast amounts of information that is encoded in the local abundance and functional state of a multitude of biomolecules acting as cell state sensors and transmitters. Recent advances in our understanding of cell regulation have suggested that a substantial portion of the interactions that facilitate conditional and dynamic cellular decision-making in higher Eukaryotes are mediated by compact and degenerate interaction modules known as motifs (short linear motifs (SLiMs) in proteins, RNA motifs in RNA and regulatory elements in DNA) [1–5]. The term motif denotes a repeated figure or design and, in motif biology, the occurrence of a given class of motif in a set of unrelated biomolecules led to the appropriation of the term to refer to a recurrent pattern of nucleotides or amino acids that corresponds to an autonomous functional module.
The higher eukaryotic cell has an extensive repertoire of DNA, RNA and peptide motifs that function as dynamic binding modules in complex formation, recruiters of basal regulatory pathways, or receivers of cell state information through association with or modification by their interaction partner [6–8]. These motifs control many aspects of transcriptional (recruiting the basal transcription machinery and transcriptional regulators to the numerous promoters, enhancers, silencers and insulators [6, 9–12]), post-transcriptional (controlling protein production by modulating pre-mRNA splicing; mRNA stability, storage and localisation; and microRNA (miRNA) recruitment [7, 13–17]) and post-translational regulation (controlling a protein’s stability, localisation, modification state and complex association [1, 8, 18, 19]) (Table 1). The regulatory regions of most genes, (pre-)mRNAs and proteins have extensively exploited the available motif repertoire [8, 20, 21] and each biomolecule contains a distinct set of motifs that encode unique regulatory programs tuned to govern the life cycle of the biomolecule . These motifs often occur with high densities as the compact footprint of sequence motifs allows multiple functional modules to be encoded in a short polypeptide or polynucleotide segment [2, 4, 5, 23, 24].
Experimental and bioinformatics studies are beginning to offer an insight into the mechanisms driving motif acquisition [4, 25–34]. Many instances are undoubtedly the product of duplication or recombination [25, 31, 35–37]. Conversely, substantial indirect evidence from the comparison of motif presence in different species suggests that motifs can be gained and lost relatively rapidly in homologous regions [26, 27, 31, 34, 38–41]. This observed evolutionary plasticity, in association with their degenerate nature and the limited number of affinity- and specificity-determining residues in a motif, led to the hypothesis that novel motif instances are often acquired through ex nihilo motif evolution by point mutations, insertions or deletions [27, 31, 32, 42]. However, catching evolution in the act is difficult. For SLiMs, a serine to glycine mutation in Leucine-rich repeat protein SHOC-2 (SHOC2), which results in a novel myristoylation motif and causes aberrant SHOC2 localisation, provides the sole experimentally characterised example of ex nihilo motif birth on the protein level . The mutation is found in several patients with Noonan-like syndrome and for some, the sequence variation is present in neither parents. Thus, the birth of this novel motif is often the result of a germline mutation. A similar mechanism of ex nihilo motif acquisition has been hypothesised for nucleotide motifs [31–33]. Indeed, the probability of a motif occurring by chance at a given position is equivalent for the motifs of the three major classes of biomolecule. Consequently, though the three major types of motif are physicochemically distinct they share a similar evolutionary plasticity that has resulted in the ubiquity that gave them their shared name.
The human proteome contains thousands of motif-binding proteins. The current census of nucleotide motif-binding proteins stands at ~1400 DNA-binding proteins  and ~850 RNA-binding proteins . The number of SLiM-binding proteins remains to be elucidated, however, given the distribution of known SLiM-binding and -modifying domains in the human proteome, it is likely to be in a similar range [8, 45]. This would suggest that upwards of 20 % of the human proteome might consist of motif-binding proteins. Furthermore, ~2000 human RNA motif-recognising miRNAs have been annotated . Hundreds of distinct classes of motifs recognised by motif-binding biomolecules have been characterised to date [6–8]. The simplicity of motif acquisition has driven the proliferation of motifs of widespread utility and, for several motif classes, experimentally characterised motif instances are present in tens of biomolecules [6, 8, 47]. For a handful of classes, hundreds, or even thousands, of motif instances are known [11, 48, 49]. On the protein level, the high motif density of well-characterised biomolecules , the extensive regions of intrinsic disorder  (where SLiMs are the predominant functional module type [1, 51]) and the numerous SLiM-binding domains  suggest extensive motif use in complex organisms. Recently, Tompa et al. hypothesised that the human proteome may contain up to a million SLiMs , however, the actual number of motifs is unknown. The reason is simple, SLiM discovery is difficult: computational approaches have high false positive rates and experimental techniques must overcome the transience of SLiM-mediated interactions, extensive SLiM co-operativity, redundancy and weak phenotypes . However, recent advances in experimental discovery techniques, particularly high-throughput discovery methods, will hopefully rectify this in the coming decade .
In this review, while focusing on SLiMs, we aim to highlight the similarities in the use of motif co-regulation and co-operativity in transcriptional, post-transcriptional and post-translational regulation. We discuss how the evolutionary plasticity of sequence motifs facilitated their proliferation and supported the evolution of extensive networks of co-regulation. We examine how the ability to readily add a functional module without disturbing a pre-existing regulatory interface promotes high functional density and how motifs can functionally modulate each other to create decision-making interfaces capable of integrating cell state information. Finally, we consider how multiple motif-containing interfaces in the same biomolecule collaborate to create unique regulatory programs.
Data from genome sequencing projects has failed to reveal the anticipated correlation between biological complexity and proteome size . This led to the hypothesis that the emergence of increasingly complex organisms was facilitated by an increase in regulation rather than protein number [55–58]. But what supports the increased complexity of regulation in the higher eukaryotic cell?
One key feature of eukaryotic regulation is the extensive reuse of specialised regulatory pathways. The ease of motif acquisition, facilitated by their evolutionary plasticity, makes them the ideal module to simplify access to systems of widespread utility, and evolution appears to have exploited this extensively. Accordingly, many motifs encode the ability to recruit components of these regulatory systems (Table 1). The intrinsic evolutionary properties of motifs have facilitated the evolution of large networks of biomolecules that bind to a single motif-binding hub acting as recognition element for the regulatory machinery (for instance, gene promoters containing hypoxia response elements (HREs) recruit the HIF-1 complex to induce expression of genes involved in the response to limited oxygen conditions ; co-regulation of the translation and stability of mRNAs encoding proteins involved in iron metabolism by iron-responsive elements (IREs) in the untranslated regions (UTRs) that bind iron regulatory proteins depending on iron availability ; concerted degradation of cell cycle regulatory proteins in a cell cycle phase-dependent manner through recognition of specific degron motifs by the Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase ). As a result, instances of the same motif class are regularly present in multiple distinct biomolecules [8, 30, 48, 62] (a motif class defines the set of motifs that recognise a single motif-binding pocket on a specific biomolecule). Interestingly, these networks are evolutionarily dynamic and differ between even closely related species [27, 41, 63]; however, it appears that once a functionally valuable motif-accessible system is in place, additional biomolecules come under the control of these systems, thereby extending the regulatory networks (Fig. 1a) . Most of the more abundant motifs link biomolecules to the molecular machinery that performs important basal house keeping functions. Basal functions can be required by thousands of biomolecules and consequently many of the motifs that facilitate these functions are ubiquitous (for example, the motifs that recruit the basal transcription, splice site recognition and protein translocation machinery [48, 49, 62]) (Fig. 1b). An important subset of the regulatory machinery is the conditionally, temporally or spatially restricted motif-binding molecules that transmit cell state information to the motif-containing biomolecule (Fig. 1c and d). The cell contains numerous motif-accessible pathways that allow biomolecules to integrate cell state information in their interfaces to respond appropriately and in a coordinated manner to changes in their environment (for example, fluctuations in calcium levels [64–66] (Fig. 1f), transitions of cell cycle phase [41, 67–69] or detection of DNA damage [70, 71]). On the protein level, motif-binding pockets can also recruit several distinct motif-containing regulatory proteins to a complex. In these cases, the motif facilitates the construction of functionally distinct assemblies around a constant complex core, for example, the recruitment of PIP box motif-containing proteins to the DNA sliding clamp by Proliferating cell nuclear antigen (PCNA) [72, 73] (Fig. 1e), the recruitment of SxIP motif-containing proteins to microtubule plus-end binding proteins , or the recruitment of LxCxE motif-containing proteins to E2F-regulated promoters by Retinoblastoma-associated protein (Rb) .
Thus, the evolutionary properties of motifs simplify access to many, widely relevant functionalities and facilitate the construction of diverse functional assemblies around a constant complex core. The higher eukaryotic cell contains innumerable co-regulated networks of biomolecules that are connected by motifs. Experimental analyses of these networks should consider that the modulation of a single motif could have effects across the network.
Motifs are autonomous functional binding modules that can independently engage in an interaction. Many motifs can function in isolation, however, in many cases, a binding or modification event at one motif will affect binding to or modification of another motif, i.e. motifs generally act co-operatively. Multiple distinct motif-mediated binding and/or modification events can affect each other either positively or negatively to various degrees, i.e. they can induce, promote, inhibit or completely abrogate each other. The cell extensively exploits motif co-operativity and to date, many experimentally validated cases of co-operative binding of motifs have been described . Co-operative binding can serve to increase the specificity of an interaction, to increase the affinity of an interaction, and/or to integrate cell state information, as will be described in the following paragraphs [1, 4].
A common strategy in motif interactions is the co-operative binding of multiple motifs and motif-binding domains, which in isolation are somewhat promiscuous, to mediate highly specific interactions. Motif-binding domains or motifs can co-operate at an intermolecular level, through multimerisation of the motif-binding or motif-containing partners  (Fig. 2a), or at an intramolecular level, for example many motif-binding domains (e.g. zinc fingers for DNA motifs, RNA recognition motifs (RRM) for RNA motifs, and SH2, SH3 and PDZ domains for SLiMs) occur as tandem arrays to increase binding specificity [77–79] (Fig. 2b). In proteins, multiple pockets on the same globular domain can also function co-operatively  (Fig. 2c). These mechanisms, in addition to temporal and spatial separation of biomolecules , permit high-fidelity recognition of biologically relevant binding partners despite the large number of sequences that are complementary to the specificity of a single motif-binding module . The same mechanisms also allow the intrinsically weak affinities of a single motif (a particular feature of SLiMs, which mediate interactions with affinities that are generally in the 1–10 μM range) to be increased by binding multivalently with high avidity. The binding strength of these interactions can increase by orders of magnitude while the system retains much of the dynamism of the constituent parts [82, 83]. For instance, robust localisation of Amphiphysin 1 to the periphery of assembling clathrin lattices depends on two distinct motifs that bind to two independent sites on the N-terminal beta-propeller domain of clathrin, which increases the affinity and specificity of the interaction . Similarly, higher order use of co-operative avidity-driven binding mechanisms also allows motifs to recruit, organise and stabilise large dynamic multimeric complexes such as those that assemble at DNA regulatory element-rich gene promoters  or on SLiM-rich scaffolding proteins [1, 85].
In addition to directing multi-partite interactions with high specificity and avidity, motif co-operativity also plays a fundamental role in cellular decision-making. A single motif instance is not intrinsically conditional. However, through regulation of the local abundance of the motif-binding partner and/or through co-operative or competitive use of multiple motifs, combinatorial decision-making is possible . A binding or modification event at one motif can modulate the occupancy state of another motif, thus changing the functionality of the second motif. Accordingly, the co-operative nature of their interactions provides motifs the means to integrate cell state information from multiple inputs and propagate regulatory decisions based on this information. Binding motifs can influence each other in different ways [18, 19]. Overlapping or adjacent motifs can promote mutually exclusive, competitive interactions, allowing context-dependent assembly of functionally distinct complexes  (Fig. 2d). For instance, in Rb, the docking motif for the catalytic subunit of protein phosphatase 1 (PP1) and the cyclin docking motif that recruits cyclin-Cdk complexes overlap. While binding to PP1 results in dephosphorylation of Rb, keeping it active as a repressor of E2F-dependent transcription, binding to cyclin-Cdk results in phosphorylation and inactivation of Rb, thus promoting cell cycle progression . Alternatively, adjacent motifs can co-operate positively, facilitating the integration of signals encoded in the presence of their different binding partners  (Fig. 2e). Such co-operativity occurs during assembly of the T cell signalling complex on the Linker for activation of T-cells family member 1 (LAT) scaffold protein, which contains multiple SH2 domain-binding motifs that, upon phosphorylation, recruit a variety of signalling proteins through their respective SH2 domains to build a functional signalling complex . Another key mechanism for cell state dependent decision-making is mediated by modulation of the intrinsic affinity and/or specificity of a motif by modification of one or more overlapping or neighbouring modification motifs [89, 90]. The binding properties of a motif can be adjusted by the covalent attachment of a moiety (Fig. 2f), ranging from switching on intrinsically inactive motifs that require a specific modification in order to be active [91, 92] (for instance, Plk1-catalysed phosphorylation of two serine residues in the beta-TrCP-binding degron in Claspin is required for its interaction with beta-TrCP and the associated ubiquitin ligase complex, resulting in ubiquitylation and subsequent proteasomal degradation of Claspin, a process involved in termination of the DNA replication checkpoint ), disrupting an interaction [94, 95] (such as binding of the USP7-docking motif in Mdm4 to the deubiquitylating enzyme USP7, which is inhibited by phosphorylation of a serine residue adjacent to the motif by ATM kinase to promote Mdm4 destabilisation during DNA damage response ) or changing the specificity of a binding region from one binding partner to another  (for example, phosphorylation of a tyrosine residue in a PTB domain-binding motif in the Integrin beta-3 tail negatively regulates integrin activation by switching the specificity of the binding region from Talin to Dok1 ). The binding properties of a motif or a motif-binding domain can also be modulated indirectly by allosteric effects, resulting from modification or effector association/dissociation at a site that is distinct from the actual interaction interface [99–101] (Fig. 2g). A well characterised example of allosteric regulation of SLiM-mediated interactions involves ligand-induced activation of the Wiskott-Aldrich syndrome protein (WAS), where binding of Cdc42 relieves a motif-mediated auto-inhibitory interaction in WAS, resulting in activation of the protein .
On a molecular level, some motifs will function independently, whereas others will be contained in multi-motif co-operative interfaces. This raises the question whether there exist pairings of motifs that can cooperate and others that cannot? Or is the requirements of the system the only limit on the observed co-operative motif pairings? The mechanisms driving the evolution of motif co-operativity is an open question and only a handful of examples of a co-operative motif being added to a pre-existant motif interface have been fully characterized [25, 39]. However, given the simplicity of motif acquisition, most motif pairings will have been tested by evolution. It is likely that unobserved pairings are of limited biological utility and consequently are not retained. It is clear that many commonly observed co-operative motif pairings reflect the available motif-binding pockets in the binding partner, for example, docking motifs and modification sites for the same PTM enzyme will often occur in the same protein, increasing the efficiency and specificity of modification [78, 80, 103–107]. Furthermore, intuitively, motifs with related functionality will be more likely to co-operate (i.e. cell cycle kinase modification motifs often regulate adjacent cell cycle-related interaction motifs such as the mitotic degron motifs [108–111]). Depending on the spatial organisation and flexibility of the motif-binding partner, constraints may be placed on the minimum or maximum inter-motif distance and the ordering of the motifs; such constraints have been observed for the APC/C and the Cdk/Cyclin/Cks1 complex [80, 112–114].
In summary, the unique evolutionary and binding attributes of motifs in DNA, RNA and proteins facilitate two highly exploited mechanisms: (i) the co-operative use of multiple independent low-affinity and low-specificity binding sites to allow highly specific assembly of dynamic, meta-stable complexes, and (ii) the co-operative integration of information in conditional decision-making interfaces. Consequently, the function of many motifs cannot be fully determined if the analysis is restricted to discrete instances.
Motif-driven regulatory programs
Evolution rarely creates completely new molecular functions, and more readily works with existing tools to produce novelty—as François Jacob stated, “Evolution is a tinkerer, not an inventor” . On the molecular level, this is clearly evident as the modular nature of biomolecules permits evolution to reuse useful modules in novel combinations to produce distinct biological outcomes .
The cell has a vast repertoire of DNA, RNA and protein motifs that carry out a wide range of functions (Table 1). Addition of these motifs can have a marked effect on a biomolecule; for example, on the protein level, addition of modules can modify the subcellular localisation, stability, modification state and interactome of a protein, hence affecting its activity and function (Fig. 3a–b). The small footprint of motifs permits the addition of a module to add novel functionality without disrupting the ancestral functionality [25, 39]. Consequently, biomolecules can contain multiple motifs [117, 118] (Table 2). As discussed in the previous section, each motif can co-operate with additional motifs and together these simple components can exhibit complex behaviour due to their conditional connectivity. The set of motifs in a biomolecule encodes a regulatory program that defines the logic of its decision-making circuitry: controlling under what conditions and to what degree transcription proceeds; the processing, location, stability and translation of RNA; and the localisation, stability, modification state and interactome of a protein. The regulatory program also defines how the biomolecule integrates the available information encoded in its own local abundance, the local abundance of its binding partners, binding site occupancy and modification state, to produce a functional outcome. Different sets of modules, or the same set of modules with distinct conditional connectivity, can respond differently to the same changes in cell state, allowing each biomolecule to build unique regulatory programs (Fig. 3c–d).
Ultimately, tens to hundreds of modules in DNA, RNA and proteins, many of them motifs, regulate the life cycle of every gene product on the transcriptional, post-transcriptional and post-translational levels from transcription to degradation (Table 2, Fig. 4) .
Biomolecules are robustly regulated from their transcription to their destruction to generate high fidelity control of cell physiology. An emerging concept in biology is that compact functional modules recognised by DNA-binding, RNA-binding and SLiM-binding biomolecules control much of the conditional decision-making in a cell [18, 120, 121]. The three major classes of biomolecules, DNA, RNA and proteins, extensively utilise short sequence motifs to determine the various aspects of their regulatory functionality and to conditionally recruit effectors based on the current cell state. Proliferation of these motifs facilitates biomolecule co-regulation and increases the complexity of cell regulation by expanding existing networks, thereby increasing the density of network wiring without any requirement to add new molecules to the proteome.
The discovery of the complete set of motifs is vital to our understanding of cell regulation. However, motifs co-operate and compete to encode the logic of decision-making and together, co-regulation and co-operativity produce intricate biological outcomes from simple motifs, generating the complicated regulation that underlies higher eukaryotic cell physiology. Consequently, to truly appreciate the regulatory program of a biomolecule, we cannot solely determine the repertoire of motifs, we must also establish the conditional connectivity between motifs. Thus, the regulatory segments of genes, the 5′-UTRs, 3′-UTRs and introns of (pre-)mRNAs, and the intrinsically disordered regions of proteins should be seen as functionally analogous regions, and the DNA regulatory elements, RNA motifs and SLiMs contained within these regions should be considered the cornerstones of regulation in complex organisms, for without them, the observed level of regulatory complexity would not be achievable.
Short linear motifs
Hypoxia response elements
RNA recognition motifs
Nuclear export signal
Protein kinase B
Nuclear localisation signal
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We apologise to all colleagues whose work could not be cited here owing to space restrictions. NED is supported by an SFI Starting Investigator Research Grant (13/SIRG/2193). We thank Holger Dinkel, Richard Edwards, Toby Gibson and Aino Järvelin for fruitful discussions and critically reading the manuscript.
The authors declare that they have no competing interests.
NED conceived the manuscript. NED and KVR wrote the manuscript. All authors read and approved the final manuscript.
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Van Roey, K., Davey, N.E. Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation. Cell Commun Signal 13, 45 (2015) doi:10.1186/s12964-015-0123-9
- Cis-regulatory elements
- RNA motifs
- Short linear motifs