Abstract
Effector proteins are bacterial virulence factors secreted directly into host cells and, through extensive interactions with host proteins, rewire host signaling pathways to the advantage of the pathogen. Despite the crucial role of globular domains as mediators of protein-protein interactions (PPIs), previous structural studies of bacterial effectors are primarily focused on individual domains, rather than domain-mediated PPIs, which limits their ability to uncover systems-level molecular recognition principles governing host-bacteria interactions. Here, we took an interaction-centric approach and systematically examined the potential of structural components within bacterial proteins to engage in or target eukaryote-specific domain-domain interactions (DDIs). Our results indicate that: 1) effectors are about six times as likely as non-effectors to contain host-like domains that mediate DDIs exclusively in eukaryotes; 2) the average domain in effectors is about seven times as likely as that in non-effectors to co-occur with DDI partners in eukaryotes rather than in bacteria; and 3) effectors are about nine times as likely as non-effectors to contain bacteria-exclusive domains that target host domains mediating DDIs exclusively in eukaryotes. Moreover, in the absence of host-like domains or among pathogen proteins without domain assignment, effectors harbor a higher variety and density of short linear motifs targeting host domains that mediate DDIs exclusively in eukaryotes. Our study lends novel quantitative insight into the structural basis of effector-induced perturbation of host-endogenous PPIs and may aid in the design of selective inhibitors of host-pathogen interactions.
Highlights
An important goal of systems microbiology is to understand how host-pathogen protein-protein interactions (PPIs) impact host-endogenous signaling networks
We acquired eukaryote-endogenous, bacteria-endogenous and host-bacteria PPI data, and resolved each PPI into domain-domain interactions (DDIs) between interacting proteins, based on DDI templates previously derived from 3D structures of protein complexes (Materials and Methods)
We found that of the 103 host-targeting bacterial proteins, 95 (92%) bind to the same domains on their host target that are otherwise bound by host-endogenous proteins, suggesting that like viruses, bacteria tend to recruit domains involved in host-endogenous PPIs for host-pathogen PPIs (Cazalet et al, 2004)
Summary
An important goal of systems microbiology is to understand how host-pathogen protein-protein interactions (PPIs) impact host-endogenous signaling networks. Host-Interacting Modules in Bacterial Effectors host signaling pathways This functional mimicry can be achieved in one of two ways: horizontal acquisition of eukaryotic globular domains, or convergent evolution of domains and short linear motifs in bacteria that bear little sequence or structural similarity to eukaryotic proteins (Stebbins and Galan, 2001; Popa et al, 2016; Scott and Hartland, 2017). These structural modules allow effectors to interact seamlessly with host-endogenous factors involved in actin remodelling, protein degradation and cell cycle regulation, helping the pathogen to survive and thrive in the host while bypassing immune surveillance. Despite studies pointing to the presence of many eukaryotic-like domains in bacterial effectors, there has yet to be a comprehensive, quantitative analysis of the relevance of such domains to host-endogenous PPIs, which is crucial to understanding systems-level changes in the host upon infection with pathogens
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