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Dissecting the Specificity of Protein-Protein Interaction in Bacterial Two-Component Signaling: Orphans and Crosstalks

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  • Andrea Procaccini
  • Bryan Lunt
  • Hendrik Szurmant
  • Terence Hwa
  • Martin Weigt

Abstract

Predictive understanding of the myriads of signal transduction pathways in a cell is an outstanding challenge of systems biology. Such pathways are primarily mediated by specific but transient protein-protein interactions, which are difficult to study experimentally. In this study, we dissect the specificity of protein-protein interactions governing two-component signaling (TCS) systems ubiquitously used in bacteria. Exploiting the large number of sequenced bacterial genomes and an operon structure which packages many pairs of interacting TCS proteins together, we developed a computational approach to extract a molecular interaction code capturing the preferences of a small but critical number of directly interacting residue pairs. This code is found to reflect physical interaction mechanisms, with the strongest signal coming from charged amino acids. It is used to predict the specificity of TCS interaction: Our results compare favorably to most available experimental results, including the prediction of 7 (out of 8 known) interaction partners of orphan signaling proteins in Caulobacter crescentus. Surveying among the available bacterial genomes, our results suggest 15∼25% of the TCS proteins could participate in out-of-operon “crosstalks”. Additionally, we predict clusters of crosstalking candidates, expanding from the anecdotally known examples in model organisms. The tools and results presented here can be used to guide experimental studies towards a system-level understanding of two-component signaling.

Suggested Citation

  • Andrea Procaccini & Bryan Lunt & Hendrik Szurmant & Terence Hwa & Martin Weigt, 2011. "Dissecting the Specificity of Protein-Protein Interaction in Bacterial Two-Component Signaling: Orphans and Crosstalks," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-9, May.
    • Handle: RePEc:plo:pone00:0019729
    DOI: 10.1371/journal.pone.0019729
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    1. Emanuele G. Biondi & Sarah J. Reisinger & Jeffrey M. Skerker & Muhammad Arif & Barrett S. Perchuk & Kathleen R. Ryan & Michael T. Laub, 2006. "Regulation of the bacterial cell cycle by an integrated genetic circuit," Nature, Nature, vol. 444(7121), pages 899-904, December.
    2. Lukas Burger & Erik van Nimwegen, 2010. "Disentangling Direct from Indirect Co-Evolution of Residues in Protein Alignments," PLOS Computational Biology, Public Library of Science, vol. 6(1), pages 1-18, January.
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    2. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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    4. Ross D. Jones & Yili Qian & Katherine Ilia & Benjamin Wang & Michael T. Laub & Domitilla Del Vecchio & Ron Weiss, 2022. "Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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