Structural Profiling of Bacterial Effectors Reveals Enrichment of Host-Interacting Domains and Motifs

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.

Definition of the effector landscape across 13 Phytoplasma proteomes with LEAPH and EffectorComb

“…This modulation of gene expression relies on the secretion of specific pathogenicity factors called effector proteins. Effectors' arsenal and their delivery system vary from species to species although they have the common aim to interfere with the host metabolism to their advantage, and to hamper the immune system, enhancing the pathogen survival and the development of the disease (10)(11)(12)(13). Advancing our knowledge about the functioning and success of biotic interactions is of prime importance towards improving plant health globally in an environmentally friendly context.…”

ImitateDB: A database for domain and motif mimicry incorporating host and pathogen protein interactions

“…Hijacking of host networks by the pathogen essentially works by imitation and competition with endogenous host–host interactions (Franzosa and Xia 2011 ; Yapici-Eser et al 2021 ). It has been observed that a majority of the pathogen proteins bind to the same domain on their respective host target that are otherwise bound by host endogenous proteins (Chen and Xia 2021 ). In addition to employing mimicking host domains, effectors also employ short linear motifs that bind to host domains with similar specificities as host endogenous proteins, albeit sharing little homology with the latter(Samano-Sanchez and Gibson 2020 ).…”

Quantification of Adaptive Immune Responses Against Protein-Binding Interfaces in the Streptococcal M1 Protein

“…Such information has paved the way for system-level analyses of whole interactomes, leading to a better understanding of pathogenicity, disease progression, and human-pathogen coevolution ( 16 ). Further, the development of chemical crosslinking mass spectrometry (XL-MS) ( 17 , 18 ) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) ( 19 , 20 ) has increased the resolution of these interactions by catalyzing the identification of protein-binding interfaces, which is of relevance for the uncovering of systems-level molecular recognition principles governing host-bacteria interactions ( 21 ). In addition, the accumulation of host-pathogen protein-protein interaction interfaces provides new opportunities to investigate the relationship between antibody responses and protein binding interfaces.…”