The Robustness of a Signaling Complex to Domain Rearrangements Facilitates Network Evolution
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{"title"=>"The Robustness of a Signaling Complex to Domain Rearrangements Facilitates Network Evolution", "type"=>"journal", "authors"=>[{"first_name"=>"Paloma M.", "last_name"=>"Sato", "scopus_author_id"=>"56536424400"}, {"first_name"=>"Kogulan", "last_name"=>"Yoganathan", "scopus_author_id"=>"56536499800"}, {"first_name"=>"Jae H.", "last_name"=>"Jung", "scopus_author_id"=>"56535705600"}, {"first_name"=>"Sergio G.", "last_name"=>"Peisajovich", "scopus_author_id"=>"6602949002"}], "year"=>2014, "source"=>"PLoS Biology", "identifiers"=>{"sgr"=>"84924072714", "doi"=>"10.1371/journal.pbio.1002012", "pui"=>"602601605", "pmid"=>"25490747", "scopus"=>"2-s2.0-84924072714", "issn"=>"15457885", "isbn"=>"1545-7885"}, "id"=>"febbff58-282b-3df8-94a6-a02de61a328e", "abstract"=>"The rearrangement of protein domains is known to have key roles in the evolution of signaling networks and, consequently, is a major tool used to synthetically rewire networks. However, natural mutational events leading to the creation of proteins with novel domain combinations, such as in frame fusions followed by domain loss, retrotranspositions, or translocations, to name a few, often simultaneously replace pre-existing genes. Thus, while proteins with new domain combinations may establish novel network connections, it is not clear how the concomitant deletions are tolerated. We investigated the mechanisms that enable signaling networks to tolerate domain rearrangement-mediated gene replacements. Using as a model system the yeast mitogen activated protein kinase (MAPK)-mediated mating pathway, we analyzed 92 domain-rearrangement events affecting 11 genes. Our results indicate that, while domain rearrangement events that result in the loss of catalytic activities within the signaling complex are not tolerated, domain rearrangements can drastically alter protein interactions without impairing function. This suggests that signaling complexes can maintain function even when some components are recruited to alternative sites within the complex. Furthermore, we also found that the ability of the complex to tolerate changes in interaction partners does not depend on long disordered linkers that often connect domains. Taken together, our results suggest that some signaling complexes are dynamic ensembles with loose spatial constraints that could be easily re-shaped by evolution and, therefore, are ideal targets for cellular engineering.", "link"=>"http://www.mendeley.com/research/robustness-signaling-complex-domain-rearrangements-facilitates-network-evolution", "reader_count"=>46, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>2, "Other"=>3, "Student > Master"=>5, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>2, "Other"=>3, "Student > Master"=>5, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>12, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>1, "Social Sciences"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>3, "Brazil"=>2, "United Kingdom"=>1, "France"=>2}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1831708"], "description"=>"<p>(A) Differentiating between two alternative hypotheses: removal of IDRs should negatively impact signaling function if the signaling complex possesses well-defined spatial constraints and therefore a rather rigid structure (left). In contrast, removal of IDRs could be tolerated if the complex is flexible and can adopt a wide ensemble of conformations (right). (B) Schematic representation of the IDR deletion variants. (C) Mating pathway function in yeast strains with IDR-deleted Ste11, Ste20, or Ste50 variants (“Short”), relative to their corresponding full-length variants. (D) Mating pathway function in yeast strains with pairs of simultaneously IDR-deleted variants (either Ste11 and Ste20, or Ste11 and Ste50) in the respective double KO, relative to their corresponding full-length variants. (E) Mating pathway function in yeast strains with IDR-deleted domain rearrangement variants. Statistically significant differences are marked with asterisks. Data shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s017\" target=\"_blank\">Data S1</a>.</p>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266057, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1002012.g004", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Exploring_the_mechanisms_that_enable_signaling_complexes_to_tolerate_rearrangement_mediated_gene_replacements_/1266057", "title"=>"Exploring the mechanisms that enable signaling complexes to tolerate rearrangement-mediated gene replacements.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-09 02:53:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/1831699"], "description"=>"<p>(A) Comparison of mating pathway activation by kinase variants with or without N-t localization domains. In all cases, deletion of the full length kinase gene results in pathway inactivation. Expression of kinase variants lacking N-t localization domains only recovers partial pathway activation. In contrast, rearrangement events that fuse N-t domains known to interact with diverse partners in the mating signaling complex to the C-t kinase domains restore pathway activation to higher levels. (B) Schematic representation of the mutations introduced in Ste50 SAM domain, Ste5 RING domain, and Ste20 PBD domain. (C) Pathway activity for domain rearrangement variants carrying the mutations shown in (B) relative to the activity of the corresponding non-mutated variants. In most cases, mutations that disrupt specific recruitment interactions decrease pathway activation between 40%–50%. MUT Ste20[N]-Ste50[C] might still localize to the signaling complex, as Ste50's RA domain binds Cdc42 independently of Ste20's PBD domain <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012-Truckses1\" target=\"_blank\">[53]</a>. (D) Fluorescence microscopy of GFP-tagged domain rearrangement variants shows that kinases can be recruited to the mating shmoo using alternative interaction domains. Statistically significant differences are marked with asterisks. Data shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s017\" target=\"_blank\">Data S1</a>.</p>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266051, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1002012.g003", "stats"=>{"downloads"=>0, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinases_are_recruited_to_the_signaling_complex_by_alternative_N_t_localization_domains_/1266051", "title"=>"Kinases are recruited to the signaling complex by alternative N-t localization domains.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-09 02:53:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/1831713"], "description"=>"<p>(A) Schematic representation of the reciprocally rearranged variants. (B) Co-expression of Ste20[N]-Ste11[C]+Ste11[N]-Ste20[C] restores pathway activation in the Ste20Δ Ste11Δ strain, co-expression of Ste7[N]-Ste11[C]+Ste11[N]-Ste7[C] restores pathway activation in the Ste7Δ Ste11Δ strain, and co-expression of Ste50[N]-Ste11[C]+Ste11[N]-Ste50[C] restores pathway activation in the Ste50Δ Ste11Δ strain. (C) Changes in network topology resulting from domain rearrangement events in our experiments, mimic changes in network topology that have occurred during evolution. (D) Expression of the domain rearranged variant Ste20[N]-Ste11[C] in the double deletion strain Ste50Δ Ste11Δ rescues pathway activation. Statistically significant differences are marked with asterisks. Data shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s017\" target=\"_blank\">Data S1</a>.</p>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266062, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1002012.g005", "stats"=>{"downloads"=>0, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Signaling_complexes_can_tolerate_multiple_rearrangement_mediated_gene_replacements_/1266062", "title"=>"Signaling complexes can tolerate multiple rearrangement-mediated gene replacements.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-09 02:53:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/1831776", "https://ndownloader.figshare.com/files/1831777", "https://ndownloader.figshare.com/files/1831778", "https://ndownloader.figshare.com/files/1831779", "https://ndownloader.figshare.com/files/1831780", "https://ndownloader.figshare.com/files/1831781", "https://ndownloader.figshare.com/files/1831782", "https://ndownloader.figshare.com/files/1831783", "https://ndownloader.figshare.com/files/1831785", "https://ndownloader.figshare.com/files/1831786", "https://ndownloader.figshare.com/files/1831787", "https://ndownloader.figshare.com/files/1831788", "https://ndownloader.figshare.com/files/1831789", "https://ndownloader.figshare.com/files/1831790", "https://ndownloader.figshare.com/files/1831791", "https://ndownloader.figshare.com/files/1831792", "https://ndownloader.figshare.com/files/1831793", "https://ndownloader.figshare.com/files/1831794", "https://ndownloader.figshare.com/files/1831795", "https://ndownloader.figshare.com/files/1831796"], "description"=>"<div><p>The rearrangement of protein domains is known to have key roles in the evolution of signaling networks and, consequently, is a major tool used to synthetically rewire networks. However, natural mutational events leading to the creation of proteins with novel domain combinations, such as <i>in frame</i> fusions followed by domain loss, retrotranspositions, or translocations, to name a few, often simultaneously replace pre-existing genes. Thus, while proteins with new domain combinations may establish novel network connections, it is not clear how the concomitant deletions are tolerated. We investigated the mechanisms that enable signaling networks to tolerate domain rearrangement-mediated gene replacements. Using as a model system the yeast mitogen activated protein kinase (MAPK)-mediated mating pathway, we analyzed 92 domain-rearrangement events affecting 11 genes. Our results indicate that, while domain rearrangement events that result in the loss of catalytic activities within the signaling complex are not tolerated, domain rearrangements can drastically alter protein interactions without impairing function. This suggests that signaling complexes can maintain function even when some components are recruited to alternative sites within the complex. Furthermore, we also found that the ability of the complex to tolerate changes in interaction partners does not depend on long disordered linkers that often connect domains. Taken together, our results suggest that some signaling complexes are dynamic ensembles with loose spatial constraints that could be easily re-shaped by evolution and, therefore, are ideal targets for cellular engineering.</p></div>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266108, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002012.s001", "https://dx.doi.org/10.1371/journal.pbio.1002012.s002", "https://dx.doi.org/10.1371/journal.pbio.1002012.s003", "https://dx.doi.org/10.1371/journal.pbio.1002012.s004", "https://dx.doi.org/10.1371/journal.pbio.1002012.s005", "https://dx.doi.org/10.1371/journal.pbio.1002012.s006", "https://dx.doi.org/10.1371/journal.pbio.1002012.s007", "https://dx.doi.org/10.1371/journal.pbio.1002012.s008", "https://dx.doi.org/10.1371/journal.pbio.1002012.s009", "https://dx.doi.org/10.1371/journal.pbio.1002012.s010", "https://dx.doi.org/10.1371/journal.pbio.1002012.s011", "https://dx.doi.org/10.1371/journal.pbio.1002012.s012", "https://dx.doi.org/10.1371/journal.pbio.1002012.s013", "https://dx.doi.org/10.1371/journal.pbio.1002012.s014", "https://dx.doi.org/10.1371/journal.pbio.1002012.s015", "https://dx.doi.org/10.1371/journal.pbio.1002012.s016", "https://dx.doi.org/10.1371/journal.pbio.1002012.s017", "https://dx.doi.org/10.1371/journal.pbio.1002012.s018", "https://dx.doi.org/10.1371/journal.pbio.1002012.s019", "https://dx.doi.org/10.1371/journal.pbio.1002012.s020"], "stats"=>{"downloads"=>10, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Robustness_of_a_Signaling_Complex_to_Domain_Rearrangements_Facilitates_Network_Evolution_/1266108", "title"=>"The Robustness of a Signaling Complex to Domain Rearrangements Facilitates Network Evolution", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-12-09 02:53:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/1831688"], "description"=>"<p>(A) Domain-rearrangement event creates a protein with a new domain combination. Still, a previous duplication ensures that at least one copy of the original gene with a pre-existing domain combination is maintained. (B) domain-rearrangement event creates a protein with a new domain combination, while simultaneously replacing a pre-existing gene. (C) The yeast mating pathway is activated by binding of a pheromone to a GPCR (Ste2 in “a” cells and Ste3 in “α” cells), which leads to the dissociation of the Gα subunit from the Gβγ subunits. Subsequent recruitment of the Ste5 scaffold brings three kinases to the membrane proximity (the MAP3K Ste11, the MAP2K Ste7, and the MAPK Fus3). The interaction of the adaptor Ste50 with the small GTPase Cdc42 connects the p21-activated kinase Ste20 to its downstream substrate Ste11, which will then initiate a phosphorylation cascade that leads to changes in gene expression and cell morphology required for mating. (D) Schematic representation of the domain rearrangement library. Each gene encoding more than one domain was split respecting domain boundaries and all possible recombinations were done as represented by blue lines (GenBank accession numbers for individual domains used to construct the library are listed in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s019\" target=\"_blank\">Data S3</a>) <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012-Peisajovich1\" target=\"_blank\">[11]</a>. (E) Subsets of the rearrangement library corresponding to all proteins containing at least one domain from a given gene (i.e., Ste11 in the example) were then transformed into a strain in which the corresponding gene (Ste11 in the example) had been deleted, thus replacing the WT gene with a library of domain rearrangement variants that include at least one domain from the deleted gene.</p>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266041, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1002012.g001", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Experimental_strategy_/1266041", "title"=>"Experimental strategy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-09 02:53:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/1831692"], "description"=>"<p>(A) Mating pathway activation was determined by flow cytometry, measuring the fluorescence intensity of a GFP reporter controlled by a mating-responsive <i>FUS1</i> promoter, 2 hours after addition of 1 µM α-factor. (B) As expected, individual deletions of the pathway components Ste50, Ste20, Ste7, Ste4, Ste11, Ste5, or Ste18 eliminate pathway activation <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012-Hartwell1\" target=\"_blank\">[51]</a>,<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012-Jenness1\" target=\"_blank\">[52]</a>. (C) Mating pathway activation for the library of domain rearrangement variants expressed in individual deletion strains. Rearrangement events that recreate WT genes are marked as “WT.” Repeated attempts to transform variant Ste50[N]-Ste18[C] failed, suggesting that it may result in cell toxicity. For a statistical analysis of the results see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s004\" target=\"_blank\">Figure S4</a>. Data shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002012#pbio.1002012.s017\" target=\"_blank\">Data S1</a>.</p>", "links"=>[], "tags"=>["Protein interactions", "11 genes", "impairing function", "interaction partners", "novel domain combinations", "Protein domains", "domain rearrangements", "domain combinations", "alternative sites", "domain rearrangement events", "novel network connections", "frame fusions", "domain loss", "model system", "synthetically rewire networks", "mapk", "protein kinase", "Signaling Complex", "Domain Rearrangements Facilitates Network Evolution", "yeast mitogen"], "article_id"=>1266044, "categories"=>["Uncategorised"], "users"=>["Paloma M. Sato", "Kogulan Yoganathan", "Jae H. Jung", "Sergio G. Peisajovich"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1002012.g002", "stats"=>{"downloads"=>0, "page_views"=>35, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_yeast_mating_pathway_is_robust_to_domain_rearrangement_mediated_gene_replacements_/1266044", "title"=>"The yeast mating pathway is robust to domain rearrangement-mediated gene replacements.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-09 02:53:51"}

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{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[]}
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