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Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation.

Van Roey K, Davey NE - Cell Commun. Signal (2015)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany. roey@embl.de.

ABSTRACT
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.

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Motif-dependent co-regulation of proteins. a Schema showing the expansion of a regulatory network. The original ancestral network will likely contain a limited number of targets. Proteins can be added to the network as they acquire the necessary motifs through ex nihilo evolution of novel motifs. Different species will have different regulatory networks [26, 28–30, 122, 123]. b Representative motif used to perform basal functionality. Importin-alpha bound to a nuclear localisation signal (NLS)-containing peptide from Myc [124] and representative examples of NLS motifs [125–130], showing the shared residues complementary to the binding pocket (side chains shown in structure) that result in the consensus sequence. c Representative motif involved in conditional transmission of cell state information to the motif-containing protein. Cyclin-A2 bound to a Cyclin docking motif in Cellular tumor antigen p53 [131] and representative examples of Cyclin docking motifs [131–135]. d Representative motif involved in conditional transmission of cell state information to the motif-containing protein. PKB beta bound to a PKB phosphorylation site peptide from Glycogen synthase kinase-3 beta [136] and representative examples of PKB phosphorylation sites [137–141]. The modified residue is shown in orange. e Representative motif used to recruit variable components to an invariant complex core. The PIP box-binding pocket of PCNA bound to a PIP box from p21 [142] and representative examples of PIP boxes [142–147]. f Examples of conditional motif-driven regulatory networks in which motifs underlie the co-regulation of multiple biomolecules in a coordinated manner to respond to changes in Ca2+ levels. Increased Ca2+ levels can result in motif-dependent phosphorylation (p+), dephosphorylation (p-) or competitive binding events (calcium/calmodulin-dependent protein kinase (CaMK) recognises Rxx[ST] [64], Calcineurin (CN) phosphatase recruits substrates through PxIxIT or LxVP docking motifs [65], and Calmodulin (CaM) recognises hydrophobic helical IQ motifs [66])
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Fig1: Motif-dependent co-regulation of proteins. a Schema showing the expansion of a regulatory network. The original ancestral network will likely contain a limited number of targets. Proteins can be added to the network as they acquire the necessary motifs through ex nihilo evolution of novel motifs. Different species will have different regulatory networks [26, 28–30, 122, 123]. b Representative motif used to perform basal functionality. Importin-alpha bound to a nuclear localisation signal (NLS)-containing peptide from Myc [124] and representative examples of NLS motifs [125–130], showing the shared residues complementary to the binding pocket (side chains shown in structure) that result in the consensus sequence. c Representative motif involved in conditional transmission of cell state information to the motif-containing protein. Cyclin-A2 bound to a Cyclin docking motif in Cellular tumor antigen p53 [131] and representative examples of Cyclin docking motifs [131–135]. d Representative motif involved in conditional transmission of cell state information to the motif-containing protein. PKB beta bound to a PKB phosphorylation site peptide from Glycogen synthase kinase-3 beta [136] and representative examples of PKB phosphorylation sites [137–141]. The modified residue is shown in orange. e Representative motif used to recruit variable components to an invariant complex core. The PIP box-binding pocket of PCNA bound to a PIP box from p21 [142] and representative examples of PIP boxes [142–147]. f Examples of conditional motif-driven regulatory networks in which motifs underlie the co-regulation of multiple biomolecules in a coordinated manner to respond to changes in Ca2+ levels. Increased Ca2+ levels can result in motif-dependent phosphorylation (p+), dephosphorylation (p-) or competitive binding events (calcium/calmodulin-dependent protein kinase (CaMK) recognises Rxx[ST] [64], Calcineurin (CN) phosphatase recruits substrates through PxIxIT or LxVP docking motifs [65], and Calmodulin (CaM) recognises hydrophobic helical IQ motifs [66])

Mentions: 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 [59]; 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 [60]; 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 [61]). 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) [48]. 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 [74], or the recruitment of LxCxE motif-containing proteins to E2F-regulated promoters by Retinoblastoma-associated protein (Rb) [75].Fig. 1


Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation.

Van Roey K, Davey NE - Cell Commun. Signal (2015)

Motif-dependent co-regulation of proteins. a Schema showing the expansion of a regulatory network. The original ancestral network will likely contain a limited number of targets. Proteins can be added to the network as they acquire the necessary motifs through ex nihilo evolution of novel motifs. Different species will have different regulatory networks [26, 28–30, 122, 123]. b Representative motif used to perform basal functionality. Importin-alpha bound to a nuclear localisation signal (NLS)-containing peptide from Myc [124] and representative examples of NLS motifs [125–130], showing the shared residues complementary to the binding pocket (side chains shown in structure) that result in the consensus sequence. c Representative motif involved in conditional transmission of cell state information to the motif-containing protein. Cyclin-A2 bound to a Cyclin docking motif in Cellular tumor antigen p53 [131] and representative examples of Cyclin docking motifs [131–135]. d Representative motif involved in conditional transmission of cell state information to the motif-containing protein. PKB beta bound to a PKB phosphorylation site peptide from Glycogen synthase kinase-3 beta [136] and representative examples of PKB phosphorylation sites [137–141]. The modified residue is shown in orange. e Representative motif used to recruit variable components to an invariant complex core. The PIP box-binding pocket of PCNA bound to a PIP box from p21 [142] and representative examples of PIP boxes [142–147]. f Examples of conditional motif-driven regulatory networks in which motifs underlie the co-regulation of multiple biomolecules in a coordinated manner to respond to changes in Ca2+ levels. Increased Ca2+ levels can result in motif-dependent phosphorylation (p+), dephosphorylation (p-) or competitive binding events (calcium/calmodulin-dependent protein kinase (CaMK) recognises Rxx[ST] [64], Calcineurin (CN) phosphatase recruits substrates through PxIxIT or LxVP docking motifs [65], and Calmodulin (CaM) recognises hydrophobic helical IQ motifs [66])
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666095&req=5

Fig1: Motif-dependent co-regulation of proteins. a Schema showing the expansion of a regulatory network. The original ancestral network will likely contain a limited number of targets. Proteins can be added to the network as they acquire the necessary motifs through ex nihilo evolution of novel motifs. Different species will have different regulatory networks [26, 28–30, 122, 123]. b Representative motif used to perform basal functionality. Importin-alpha bound to a nuclear localisation signal (NLS)-containing peptide from Myc [124] and representative examples of NLS motifs [125–130], showing the shared residues complementary to the binding pocket (side chains shown in structure) that result in the consensus sequence. c Representative motif involved in conditional transmission of cell state information to the motif-containing protein. Cyclin-A2 bound to a Cyclin docking motif in Cellular tumor antigen p53 [131] and representative examples of Cyclin docking motifs [131–135]. d Representative motif involved in conditional transmission of cell state information to the motif-containing protein. PKB beta bound to a PKB phosphorylation site peptide from Glycogen synthase kinase-3 beta [136] and representative examples of PKB phosphorylation sites [137–141]. The modified residue is shown in orange. e Representative motif used to recruit variable components to an invariant complex core. The PIP box-binding pocket of PCNA bound to a PIP box from p21 [142] and representative examples of PIP boxes [142–147]. f Examples of conditional motif-driven regulatory networks in which motifs underlie the co-regulation of multiple biomolecules in a coordinated manner to respond to changes in Ca2+ levels. Increased Ca2+ levels can result in motif-dependent phosphorylation (p+), dephosphorylation (p-) or competitive binding events (calcium/calmodulin-dependent protein kinase (CaMK) recognises Rxx[ST] [64], Calcineurin (CN) phosphatase recruits substrates through PxIxIT or LxVP docking motifs [65], and Calmodulin (CaM) recognises hydrophobic helical IQ motifs [66])
Mentions: 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 [59]; 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 [60]; 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 [61]). 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) [48]. 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 [74], or the recruitment of LxCxE motif-containing proteins to E2F-regulated promoters by Retinoblastoma-associated protein (Rb) [75].Fig. 1

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany. roey@embl.de.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus