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The robustness of a signaling complex to domain rearrangements facilitates network evolution.

Sato PM, Yoganathan K, Jung JH, Peisajovich SG - PLoS Biol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Systems Biology, and Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada.

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.

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Signaling complexes can tolerate multiple rearrangement-mediated gene replacements.(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 Data S1.
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pbio-1002012-g005: Signaling complexes can tolerate multiple rearrangement-mediated gene replacements.(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 Data S1.

Mentions: We hypothesized that if signaling complexes possess loosely defined spatial constraints, the network should tolerate more complex domain rearrangement events, such as those in which domains from pairs of proteins are reciprocally rearranged (Figure 5A). To test this hypothesis, we introduced the pairs of reciprocally rearranged variants Ste20[N]-Ste11[C]+Ste11[N]-Ste20[C], Ste7[N]-Ste11[C]+Ste11[N]-Ste7[C], and Ste50[N]-Ste11[C]+Ste11[N]-Ste50[C], in the double deletion strains Ste20Δ Ste11Δ, Ste7Δ Ste11Δ, and Ste50Δ Ste11Δ, respectively. As shown in Figure 5B, while transformation with any of the single domain rearrangement variants did not rescue the double deletions, transformation with each pair of reciprocally rearranged variants rescued pathway activation, demonstrating that the mating signaling complex can accommodate changes in domain connectivity in two components simultaneously, supporting the hypothesis that the signaling complex does not possess a rigid, precisely defined geometry.


The robustness of a signaling complex to domain rearrangements facilitates network evolution.

Sato PM, Yoganathan K, Jung JH, Peisajovich SG - PLoS Biol. (2014)

Signaling complexes can tolerate multiple rearrangement-mediated gene replacements.(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 Data S1.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4260825&req=5

pbio-1002012-g005: Signaling complexes can tolerate multiple rearrangement-mediated gene replacements.(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 Data S1.
Mentions: We hypothesized that if signaling complexes possess loosely defined spatial constraints, the network should tolerate more complex domain rearrangement events, such as those in which domains from pairs of proteins are reciprocally rearranged (Figure 5A). To test this hypothesis, we introduced the pairs of reciprocally rearranged variants Ste20[N]-Ste11[C]+Ste11[N]-Ste20[C], Ste7[N]-Ste11[C]+Ste11[N]-Ste7[C], and Ste50[N]-Ste11[C]+Ste11[N]-Ste50[C], in the double deletion strains Ste20Δ Ste11Δ, Ste7Δ Ste11Δ, and Ste50Δ Ste11Δ, respectively. As shown in Figure 5B, while transformation with any of the single domain rearrangement variants did not rescue the double deletions, transformation with each pair of reciprocally rearranged variants rescued pathway activation, demonstrating that the mating signaling complex can accommodate changes in domain connectivity in two components simultaneously, supporting the hypothesis that the signaling complex does not possess a rigid, precisely defined geometry.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Systems Biology, and Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada.

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.

Show MeSH
Related in: MedlinePlus