Abstract
A central challenge in host-pathogen systems biology is the elucidation of general, systems-level principles that distinguish host-pathogen interactions from within-host interactions. Current analyses of host-pathogen and within-host protein-protein interaction networks are largely limited by their resolution, treating proteins as nodes and interactions as edges. Here, we construct a domain-resolved map of human-virus and within-human protein-protein interaction networks by annotating protein interactions with high-coverage, high-accuracy, domain-centric interaction mechanisms: (1) domain-domain interactions, in which a domain in one protein binds to a domain in a second protein, and (2) domain-motif interactions, in which a domain in one protein binds to a short, linear peptide motif in a second protein. Analysis of these domain-resolved networks reveals, for the first time, significant mechanistic differences between virus-human and within-human interactions at the resolution of single domains. While human proteins tend to compete with each other for domain binding sites by means of sequence similarity, viral proteins tend to compete with human proteins for domain binding sites in the absence of sequence similarity. Independent of their previously established preference for targeting human protein hubs, viral proteins also preferentially target human proteins containing linear motif-binding domains. Compared to human proteins, viral proteins participate in more domain-motif interactions, target more unique linear motif-binding domains per residue, and contain more unique linear motifs per residue. Together, these results suggest that viruses surmount genome size constraints by convergently evolving multiple short linear motifs in order to effectively mimic, hijack, and manipulate complex host processes for their survival. Our domain-resolved analyses reveal unique signatures of pleiotropy, economy, and convergent evolution in viral-host interactions that are otherwise hidden in the traditional binary network, highlighting the power and necessity of high-resolution approaches in host-pathogen systems biology.
Highlights
Protein-protein interactions (PPIs) can be broadly classified into two fundamentally different classes: those within the same species, such as within-host protein-protein interaction (PPI), and those between different species, such as host-pathogen PPIs
Analysis of protein-protein interaction (PPI) networks can identify general principles that distinguish between within-species and betweenspecies interactions
Using protein domain-based annotation methods, we have constructed an integrated human-virus PPI network which better highlights the mechanistic differences between human-human and human-virus PPIs
Summary
Protein-protein interactions (PPIs) can be broadly classified into two fundamentally different classes: those within the same species, such as within-host PPIs, and those between different species, such as host-pathogen PPIs. Many viral proteins directly compete with host proteins for binding sites [4], and some even modify host proteins chemically, e.g. marking them for degradation by the host’s own machinery [5,6,7]. Despite providing such detailed information about the molecular mechanisms and consequences of specific exogenous interactions, traditional virology studies are highly focused and are often unable to draw general conclusions about the mechanisms governing exogenous interactions even among closely related viruses. Despite these detailed studies on specific host-virus interaction systems, the overarching principles that distinguish host-virus interactions from within-host interactions have not yet been elucidated
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