Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes

Two-component signaling (TCS) is the primary means by which bacteria sense and respond to the environment. TCS involves two partner proteins working in tandem, which interact to perform cellular functions whereas limiting interactions with non-partners (i.e., cross-talk). We construct a Potts model...

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Bibliographic Details
Published in:Molecular biology and evolution 2016-12, Vol.33 (12), p.3054-3064
Main Authors: Cheng, R R, Nordesjö, O, Hayes, R L, Levine, H, Flores, S C, Onuchic, J N, Morcos, F
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Bacteria - genetics
Bacteria - metabolism
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
bacterial signaling
Computer Simulation
epistasis
Fast Track
fitness landscape
Gene Expression Regulation, Bacterial
interaction specificity
mutational phenotypes
Phenotype
Protein Binding
Protein Kinases - metabolism
Sequence Analysis, Protein - methods
Signal Transduction - genetics
statistical inference
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Summary:Two-component signaling (TCS) is the primary means by which bacteria sense and respond to the environment. TCS involves two partner proteins working in tandem, which interact to perform cellular functions whereas limiting interactions with non-partners (i.e., cross-talk). We construct a Potts model for TCS that can quantitatively predict how mutating amino acid identities affect the interaction between TCS partners and non-partners. The parameters of this model are inferred directly from protein sequence data. This approach drastically reduces the computational complexity of exploring the sequence-space of TCS proteins. As a stringent test, we compare its predictions to a recent comprehensive mutational study, which characterized the functionality of 20 mutational variants of the PhoQ kinase in Escherichia coli We find that our best predictions accurately reproduce the amino acid combinations found in experiment, which enable functional signaling with its partner PhoP. These predictions demonstrate the evolutionary pressure to preserve the interaction between TCS partners as well as prevent unwanted cross-talk. Further, we calculate the mutational change in the binding affinity between PhoQ and PhoP, providing an estimate to the amount of destabilization needed to disrupt TCS.
ISSN:0737-4038
1537-1719
1537-1719
DOI:10.1093/molbev/msw188