Toward rationally redesigning bacterial two-component signaling systems using coevolutionary information

Ryan R. Cheng, Faruck Morcos, Herbert Levine, José N. Onuchic

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


A challenge in molecular biology is to distinguish the key subset of residues that allowtwo-component signaling (TCS) proteins to recognize their correct signaling partner such that they can transiently bind and transfer signal, i.e., phosphoryl group. Detailed knowledge of this informationwould allow one to search sequence space formutations that can be used to systematically tune the signal transmission between TCS partners as well as potentially encode a TCS protein to preferentially transfer signals to a nonpartner. Motivated by the notion that this detailed information is found in sequence data, we explore the sequence coevolution between signaling partners to better understand how mutations can positively or negatively alter their ability to transfer signal. Using direct coupling analysis for determining evolutionarily conserved protein-protein interactions, we apply a metric called the direct information score to quantify mutational changes in the interaction between TCS proteins and demonstrate that it accurately correlates with experimental mutagenesis studies probing themutational change in measured in vitro phosphotransfer. Furthermore, by subtracting from our metric an appropriate null model corresponding to generic, conserved features in TCS signaling pairs, we can isolate the determinants that give rise to interaction specificity and recognition, which are variable among different TCS partners. Our methodology forms a potential framework for the rational design of TCS systems by allowing one to quickly search sequence space for mutations or even entirely new sequences that can increase or decrease our metric, as a proxy for increasing or decreasing phosphotransfer ability between TCS proteins.

Original languageEnglish
Pages (from-to)E563-E571
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - Feb 4 2014


  • Covariation
  • Information theory
  • Protein recognition
  • Signal transduction
  • Statistical inference

ASJC Scopus subject areas

  • General


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