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Crosstalk and the Evolution of Specificity in Two-Component Signaling Corrections BIOPHYSICS AND COMPUTATIONAL BIOLOGY PLANT BIOLOGY Correction for “Crosstalk and the evolution of specificity in two- Correction for “Differential processing of Arabidopsis ubiquitin- component signaling,” by Michael A. Rowland and Eric J. Deeds, like Atg8 autophagy proteins by Atg4 cysteine proteases,” by which appeared in issue 15, April 15, 2014, of Proc Natl Acad Sci Jongchan Woo, Eunsook Park, and S. P. Dinesh-Kumar, which USA (111:5550–5555; first published March 31, 2014; 10.1073/ appeared in issue 2, January 14, 2014, of Proc Natl Acad Sci pnas.1317178111). USA (111:863–868; first published December 30, 2013; 10.1073/ The authors note that ref. 4, “Huynh TN, Stewart V (2011) pnas.1318207111). Negative control in two-component signal transduction by trans- The authors note that the following statement should be mitter phosphatase activity. Mol Microbiol 82(2):275–286.” should added to the Acknowledgments: “National Science Foundation instead appear as “Ray JC, Igoshin OA (2010) Adaptable func- Grant NSF-IOS-1258135 funded to Dr. Georgia Drakakaki sup- tionality of transcriptional feedback in bacterial two-component ported Eunsook Park.” systems. PLoS Comput Biol 6(2):e1000676.” www.pnas.org/cgi/doi/10.1073/pnas.1409947111 www.pnas.org/cgi/doi/10.1073/pnas.1408294111 CORRECTIONS www.pnas.org PNAS | June 24, 2014 | vol. 111 | no. 25 | 9325 Downloaded by guest on September 29, 2021 Crosstalk and the evolution of specificity in two-component signaling Michael A. Rowlanda and Eric J. Deedsa,b,1 aCenter for Bioinformatics and bDepartment of Molecular Biosciences, University of Kansas, Lawrence, KS 66047 Edited by Thomas J. Silhavy, Princeton University, Princeton, NJ, and approved March 7, 2014 (received for review September 11, 2013) Two-component signaling (TCS) serves as the dominant signaling growth rate and fitness in mutant cells grown under phosphate- modality in bacteria. A typical pathway includes a sensor histidine limiting conditions. It has been shown that adding crosstalk to kinase (HK) that phosphorylates a response regulator (RR), mod- TCS can reduce information transfer efficiency under certain ulating its activity in response to an incoming signal. Most HKs are conditions (24), but it remains unclear exactly why TCS pathways bifunctional, acting as both kinase and phosphatase for their are constrained from evolving crosstalk. substrates. Unlike eukaryotic signaling networks, there is very One of the most common motifs in eukaryotic signaling net- little crosstalk between bacterial TCS pathways; indeed, adding works is a pair of enzymes (e.g., a kinase and a phosphatase) crosstalk to a pathway can have disastrous consequences for cell acting on a shared substrate (Fig. 1A) (25, 26). Using mathe- fitness. It is currently unclear exactly what feature of TCS neces- matical models, we recently showed that adding multiple com- – sitates this degree of pathway isolation. In this work we used peting substrates to this type of Goldbeter Koshland (GK) loop mathematical models to show that, in the case of bifunctional HKs, would tend to induce an ultrasensitive, switch-like behavior in adding a competing substrate to a TCS pathway will always the system, which could easily have positive phenotypic con- sequences for the cell (26–29). In the work described here, we reduce response of that pathway to incoming signals. We found performed a similar analysis, extending a well-studied and vali- that the pressure to maintain cognate signaling is sufficient to dated mathematical model of bifunctional HKs (Fig. 1B) to the explain the experimentally observed “kinetic preference” of HKs case of multiple substrates (3, 4). We found that, because the HK for their cognate RRs. These findings imply a barrier to the evolution acts both as the kinase and the phosphatase in these systems, the of new HK–RR pairs, because crosstalk is unavoidable immediately addition of competing interactions with multiple RRs always BIOPHYSICS AND after the duplication of an existing pathway. We characterized a set decreases the response of the cognate RR. This is consistent with of “near-neutral” evolutionary trajectories that minimize the im- the findings of Capra et al. (23), who showed that the phenotypic COMPUTATIONAL BIOLOGY pact of crosstalk on the function of the parental pathway. These effects of their crosstalk mutant were not due to the mis- trajectories predicted that crosstalk interactions should be re- regulation of NtrX targets, but rather a direct result of decrease moved before new input/output functionalities evolve. Analysis in phosphate starvation signaling. of HK sequences in bacterial genomes provided evidence that the The pressure to maintain cognate signaling suggests the exis- selective pressures on the HK–RR interface are different from those tence of a barrier in the evolution of new TCS pathways. New experienced by the input domain immediately after duplication. HK–RR pairs can arise from the duplication of existing HK–RR This work thus provides a unifying explanation for the evolution genes, which subsequently diverge into a new pathway (21, 30). of specificity in TCS networks. There is unavoidable crosstalk immediately postduplication, which can attenuate the response to the original signal. Using our models, we characterized a set of “near-neutral” evolution- bacterial signaling | network evolution | signal specificity ary trajectories that minimize the impact of the new pair on the signaling of the parent pathway. All of these trajectories involved wo-component signaling (TCS) represents the primary sig- insulating the two pathways from one another before establishing Tnaling modality in bacteria (1). The prototypical TCS path- new input and output functionalities. To test this prediction, we way includes a membrane-bound sensor histidine kinase (HK) that autophosphorylates upon receiving an input signal. The HK Significance then binds and transfers its phosphoryl group to a response regulator (RR), which often functions directly as a transcription The global architectures of signaling networks in bacteria and factor, regulating gene expression patterns in response to the eukaryotes are remarkably different: crosstalk between path- signal (1, 2). Many HKs are bifunctional, acting as both the ki- ways is very common in eukaryotes but is very limited in bac- nase and phosphatase for their RR; the ratio of kinase to teria. Bacteria use two-component signaling (TCS) to transduce phosphatase activity, and thus the phosphorylation state of the information, relying on a single enzyme to act as both kinase and RR, is controlled by the input (1–8). phosphatase for targets. We used mathematical models to show “ ” Signaling networks in eukaryotes display extensive crosstalk, that introducing crosstalk in TCS always decreases system per- with individual kinases acting on large numbers of targets: the – formance. This indicates that the large-scale differences between kinase Cdk1, for instance, has hundreds of substrates in yeast (9 eukaryotic and bacterial networks likely derive from differences 11). Bacterial TCS networks show a remarkably different to- – in the dynamics of the fundamental motifs from which the net- pology: HKs usually act on a single target (12 17). Intensive works themselves are constructed. We further demonstrated experimental study over the past 10 years has revealed the bio- that the pressure to avoid crosstalk has influenced the evolution chemical and biophysical basis for this lack of promiscuity. In general, HKs demonstrate a strong “kinetic preference” for their of new TCS pairs, driving rapid sequence divergence in protein cognate substrates, preferentially phosphorylating them on short interaction interfaces immediately postduplication. timescales (7, 15, 16, 18–21). A relatively small number of resi- dues in the protein–protein interaction interface between HKs Author contributions: M.A.R. and E.J.D. designed research; M.A.R. performed research; and RRs is responsible for maintaining this specificity (14–16, M.A.R. and E.J.D. analyzed data; and M.A.R. and E.J.D. wrote the paper. 20–23). Recently, Capra et al. (23) demonstrated that making The authors declare no conflict of interest. just two mutations in this interface could introduce an in- This article is a PNAS Direct Submission. teraction between an HK (PhoR) and a noncognate RR (NtrX) 1To whom correspondence should be addressed. E-mail: [email protected]. in Escherichia coli. This exogenous interaction decreased phos- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. phate starvation signaling, leading to profound decreases in 1073/pnas.1317178111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1317178111 PNAS Early Edition | 1of6 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ABInput 2 ðr − 1Þ − ðKK + rKPÞ + ððr − 1Þ − ðKK + rKPÞÞ + 4ðr − 1ÞrKP Input S p = ; ðr − Þ P P 2 1 K K HK [1] P P where S* ≡ [S*]/[S]0 is the mole fraction of phosphorylated sub- S S RR RR strate, KK ≡ KM,K/[S]0 and KP ≡ KM,P/[S]0 are the Michaelis constants divided by the total concentration of substrate, and r ≡ kcat,K[K]0/kcat,P[P]0 is the ratio of the maximum velocities of P HK the enzymes (25). Because protein concentrations (and thus the Output Output saturation parameters) remain constant over short timescales CD(31), r represents the dominant response parameter. In Fig. 1C, 1.0 1.0 we considered a model of a GK loop in which an explicit input High [S][S]0 LowLow [[RR]RR]0 molecule binds
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