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

TL;DR

This study develops a computational method to decode the molecular interaction preferences in bacterial two-component signaling systems, enabling prediction of specific interactions and crosstalks, thus advancing systems biology understanding.

Contribution

It introduces a novel computational approach to identify interaction codes in bacterial TCS, predicting specificity and crosstalks from genomic data, which was previously difficult to determine experimentally.

Findings

Predicted 7 out of 8 known orphan TCS interactions in Caulobacter crescentus.

Estimated 15-25% of TCS proteins may engage in out-of-operon crosstalks.

Identified clusters of potential crosstalking TCS proteins across bacterial genomes.

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.