Analysis of Host-Bacteria Protein Interactions Reveals Conserved Domains and Motifs That Mediate Fundamental Infection Pathways

Marc Torrent Burgas, Jordi Gómez Borrego

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Adhesion and colonization of host cells by pathogenic bacteria depend on protein-protein interactions (PPIs). These interactions are interesting from the pharmacological point of view since new molecules that inhibit host-pathogen PPIs would act as new antimicrobials. Most of these interactions are discovered using high-throughput methods that may display a high false positive rate. The absence of curation of these databases can make the available data unreliable. To address this issue, a comprehensive filtering process was developed to obtain a reliable list of domains and motifs that participate in PPIs between bacteria and human cells. From a structural point of view, our analysis revealed that human proteins involved in the interactions are rich in alpha helix and disordered regions and poorer in beta structure. Disordered regions in human proteins harbor short sequence motifs that are specifically recognized by certain domains in pathogenic proteins. The most relevant domain-domain interactions were validated by AlphaFold, showing that a proper analysis of host-pathogen PPI databases can reveal structural conserved patterns. Domain-motif interactions, on the contrary, were more difficult to validate, since unstructured regions were involved, where AlphaFold could not make a good prediction. Moreover, these interactions are also likely accommodated by post-translational modifications, especially phosphorylation, which can potentially occur in 25-50% of host proteins. Hence, while common structural patterns are involved in host-pathogen PPIs and can be retrieved from available databases, more information is required to properly infer the full interactome. By resolving these issues, and in combination with new prediction tools like Alphafold, new classes of antimicrobials could be discovered from a more detailed understanding of these interactions.
Idioma originalEnglish
RevistaInternational Journal of Molecular Sciences
Estat de la publicacióPublicada - 2022


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