c6f556a46c59ee16b8521f82626404ad pmc_9569774.pdf 905d943244bdc9c8e4618e761677c3683b469f90 pmc_9569774.pdf 9a60f36711ba98fce665840fcac070c97e972b10ddc037e053a54e15ef381651 pmc_9569774.pdf Title: Analysis of Host–Bacteria Protein Interactions Reveals Conserved Domains and Motifs That Mediate Fundamental Infection Pathways Subject: 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. Keywords: pathogen; host; protein interaction; domain; motif; Alphafold Author: Jordi Gómez Borrego and Marc Torrent Burgas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Oct 9 03:15:04 2022 CEST ModDate: Sun Oct 9 03:33:54 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 5116365 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- TPNFVY+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 DZWVDS+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 NLOPCG+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 SOZKOC+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 MXTWPO+VnURWPalladioL Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 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yes yes no 254 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-07-12 02:32:09 CEST RepresentationInformation: pmc_9569774.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-10-27 02:17:03 CEST Size: 5116365 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 438 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results and Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Enriched Domains in Host Pathogen PPIs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Domain Domain Associations in Host Pathogen PPIs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Domain Motif Associations in Host Pathogen PPIs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Structural Analysis of DD and DM Associations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Virulence Factors with Ubiquitin Protein Ligase Activity as a Case Example Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Databases Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Domain and Motif Scanning Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Domain Domain (DD) and Domain Motif (DM) Interactions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Domain and Motif Enrichment Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Gene Ontology Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Structural and Conservation Analysis of Selected PPIs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Analysis of Host Bacteria Protein Interactions Reveals Conserved Domains and Motifs That Mediate Fundamental Infection Pathways Author: Jordi Gómez Borrego and Marc Torrent Burgas Subject: 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. 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