Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Resource
  • Published:

Interactome3D: adding structural details to protein networks

Abstract

Network-centered approaches are increasingly used to understand the fundamentals of biology. However, the molecular details contained in the interaction networks, often necessary to understand cellular processes, are very limited, and the experimental difficulties surrounding the determination of protein complex structures make computational modeling techniques paramount. Here we present Interactome3D, a resource for the structural annotation and modeling of protein-protein interactions. Through the integration of interaction data from the main pathway repositories, we provide structural details at atomic resolution for over 12,000 protein-protein interactions in eight model organisms. Unlike static databases, Interactome3D also allows biologists to upload newly discovered interactions and pathways in any species, select the best combination of structural templates and build three-dimensional models in a fully automated manner. Finally, we illustrate the value of Interactome3D through the structural annotation of the complement cascade pathway, rationalizing a potential common mechanism of action suggested for several disease-causing mutations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Interactome3D pipeline.
Figure 2: Structural coverage of proteins and interactions for eight organisms.
Figure 3: Benchmarking of the homology models of interactions generated by Interactome3D.
Figure 4: Structural annotation of the complement cascade.
Figure 5: Mapping disease mutations in the context of the structural interactome.

Similar content being viewed by others

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

References

  1. Lee, M.J. et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149, 780–794 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shapira, S.D. et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139, 1255–1267 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rual, J.F. et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 437, 1173–1178 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Stelzl, U. et al. A human protein-protein interaction network: a resource for annotating the proteome. Cell 122, 957–968 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ewing, R.M. et al. Large-scale mapping of human protein-protein interactions by mass spectrometry. Mol. Syst. Biol. 3, 89 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wang, X. et al. Three-dimensional reconstruction of protein networks provides insight into human genetic disease. Nat. Biotechnol. 30, 159–164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. David, A., Razali, R., Wass, M.N. & Sternberg, M.J. Protein-protein interaction sites are hot spots for disease-associated nonsynonymous SNPs. Hum. Mutat. 33, 359–363 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Dreze, M. et al. 'Edgetic' perturbation of a C. elegans BCL2 ortholog. Nat. Methods 6, 843–849 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kim, P.M., Lu, L.J., Xia, Y. & Gerstein, M.B. Relating three-dimensional structures to protein networks provides evolutionary insights. Science 314, 1938–1941 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Berman, H.M. et al. The Protein Data Bank. Nucleic Acids Res. 28, 235–242 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pieper, U. et al. ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res. 39, D465–D474 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Zhang, Y. et al. Three-dimensional structural view of the central metabolic network of Thermotoga maritima. Science 325, 1544–1549 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pache, R.A. & Aloy, P. Incorporating high-throughput proteomics experiments into structural biology pipelines: identification of the low-hanging fruits. Proteomics 8, 1959–1964 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Stein, A., Mosca, R. & Aloy, P. Three-dimensional modeling of protein interactions and complexes is going 'omics. Curr. Opin. Struct. Biol. 21, 200–208 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Walhout, A.J. et al. Protein interaction mapping in C. elegans using proteins involved in vulval development. Science 287, 116–122 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Aloy, P., Ceulemans, H., Stark, A. & Russell, R.B. The relationship between sequence and interaction divergence in proteins. J. Mol. Biol. 332, 989–998 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Aloy, P. et al. Structure-based assembly of protein complexes in yeast. Science 303, 2026–2029 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Aloy, P. & Russell, R.B. Structural systems biology: modelling protein interactions. Nat. Rev. Mol. Cell Biol. 7, 188–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Kuzu, G., Keskin, O., Gursoy, A. & Nussinov, R. Constructing structural networks of signaling pathways on the proteome scale. Curr. Opin. Struct. Biol. 22, 367–377 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Kerrien, S. et al. The IntAct molecular interaction database in 2012. Nucleic Acids Res. 40, D841–D846 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Licata, L. et al. MINT, the molecular interaction database: 2012 update. Nucleic Acids Res. 40, D857–D861 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Turinsky, A.L., Razick, S., Turner, B., Donaldson, I.M. & Wodak, S.J. Interaction databases on the same page. Nat. Biotechnol. 29, 391–393 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Stein, A., Ceol, A. & Aloy, P. 3did: identification and classification of domain-based interactions of known three-dimensional structure. Nucleic Acids Res. 39, D718–D723 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Davis, F.P. & Sali, A. PIBASE: a comprehensive database of structurally defined protein interfaces. Bioinformatics 21, 1901–1907 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Gong, S. et al. PSIbase: a database of Protein Structural Interactome map (PSIMAP). Bioinformatics 21, 2541–2543 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Finn, R.D., Marshall, M. & Bateman, A. iPfam: visualization of protein-protein interactions in PDB at domain and amino acid resolutions. Bioinformatics 21, 410–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Itzhaki, Z., Akiva, E. & Margalit, H. Preferential use of protein domain pairs as interaction mediators: order and transitivity. Bioinformatics 26, 2564–2570 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Sali, A. & Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Taylor, W.R. A deeply knotted protein structure and how it might fold. Nature 406, 916–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Venkatesan, K. et al. An empirical framework for binary interactome mapping. Nat. Methods 6, 83–90 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Mosca, R., Pons, C., Fernandez-Recio, J. & Aloy, P. Pushing structural information into the yeast interactome by high-throughput protein docking experiments. PLoS Comput. Biol. 5, e1000490 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Méndez, R., Leplae, R., De Maria, L. & Wodak, S.J. Assessment of blind predictions of protein-protein interactions: current status of docking methods. Proteins 52, 51–67 (2003).

    Article  PubMed  CAS  Google Scholar 

  33. Kanehisa, M., Goto, S., Sato, Y., Furumichi, M. & Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40, D109–D114 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Matthews, L. et al. Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res. 37, D619–D622 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Bravo, J. & Aloy, P. Target selection for complex structural genomics. Curr. Opin. Struct. Biol. 16, 385–392 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Gordo, S. et al. Stability and structural recovery of the tetramerization domain of p53–R337H mutant induced by a designed templating ligand. Proc. Natl. Acad. Sci. USA 105, 16426–16431 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhong, Q. et al. Edgetic perturbation models of human inherited disorders. Mol. Syst. Biol. 5, 321 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kiel, C. et al. Structural and functional protein network analyses predict novel signaling functions for rhodopsin. Mol. Syst. Biol. 7, 551 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Russell, R.B. & Aloy, P. Targeting and tinkering with interaction networks. Nat. Chem. Biol. 4, 666–673 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Lopes, C.T. et al. Cytoscape Web: an interactive web-based network browser. Bioinformatics 26, 2347–2348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Russel, D. et al. Putting the pieces together: integrative modeling platform software for structure determination of macromolecular assemblies. PLoS Biol. 10, e1001244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vogt, L. et al. VSIG4, a B7 family-related protein, is a negative regulator of T cell activation. J. Clin. Invest. 116, 2817–2826 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wiesmann, C. et al. Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444, 217–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Salwinski, L. et al. The Database of Interacting Proteins: 2004 update. Nucleic Acids Res. 32, D449–D451 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goll, J. et al. MPIDB: the microbial protein interaction database. Bioinformatics 24, 1743–1744 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chautard, E., Fatoux-Ardore, M., Ballut, L., Thierry-Mieg, N. & Ricard-Blum, S. MatrixDB, the extracellular matrix interaction database. Nucleic Acids Res. 39, D235–D240 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Lynn, D.J. et al. InnateDB: facilitating systems-level analyses of the mammalian innate immune response. Mol. Syst. Biol. 4, 218 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Stark, C. et al. The BioGRID Interaction Database: 2011 update. Nucleic Acids Res. 39, D698–D704 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Isserlin, R., El-Badrawi, R.A. & Bader, G.D. The Biomolecular Interaction Network Database in PSI-MI 2.5. Database (Oxford) 2011, baq037 (2011).

    Article  CAS  Google Scholar 

  50. Keshava Prasad, T.S. et al. Human Protein Reference Database–2009 update. Nucleic Acids Res. 37, D767–D772 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Côté, R.G. et al. The Protein Identifier Cross-Referencing (PICR) service: reconciling protein identifiers across multiple source databases. BMC Bioinformatics 8, 401 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. UniProt Consortium. Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res. 40, D71–D75 (2012).

  53. Orchard, S. et al. Protein interaction data curation: the International Molecular Exchange (IMEx) consortium. Nat. Methods 9, 345–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Orchard, S. et al. The minimum information required for reporting a molecular interaction experiment (MIMIx). Nat. Biotechnol. 25, 894–898 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Ceol, A. et al. MINT, the molecular interaction database: 2009 update. Nucleic Acids Res. 38, D532–D539 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Hu, P. et al. Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins. PLoS Biol. 7, e96 (2009).

    Article  PubMed  CAS  Google Scholar 

  57. Velankar, S. et al. E-MSD: an integrated data resource for bioinformatics. Nucleic Acids Res. 33, D262–D265 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Eswar, N. et al. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 31, 3375–3380 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Aloy, P. & Russell, R.B. InterPreTS: protein interaction prediction through tertiary structure. Bioinformatics 19, 161–162 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Shen, M.Y. & Sali, A. Statistical potential for assessment and prediction of protein structures. Protein Sci. 15, 2507–2524 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Punta, M. et al. The Pfam protein families database. Nucleic Acids Res. 40, D290–D301 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Eddy, S.R. Accelerated Profile HMM Searches. PLoS Comput. Biol. 7, e1002195 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Stein, A. & Aloy, P. Novel peptide-mediated interactions derived from high-resolution 3-dimensional structures. PLoS Comput. Biol. 6, e1000789 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kerrien, S. et al. Broadening the horizon–level 2.5 of the HUPO-PSI format for molecular interactions. BMC Biol. 5, 44 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Jones, S., Marin, A. & Thornton, J.M. Protein domain interfaces: characterization and comparison with oligomeric protein interfaces. Protein Eng. 13, 77–82 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Miller, S., Janin, J., Lesk, A.M. & Chothia, C. Interior and surface of monomeric proteins. J. Mol. Biol. 196, 641–656 (1987).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially supported by the Spanish Ministerio de Ciencia e Innovación (BIO2010-22073) and the European Commission under FP7 Grant Agreement 223101 (AntiPathoGN).

Author information

Authors and Affiliations

Authors

Contributions

R.M. conceived and designed the work, wrote the manuscript, developed the pipeline, analyzed the data and implemented the Interactome3D web resource. A.C. compiled the integrated interaction database used by Interactome3D and implemented the Interactome3D web resource. P.A. conceived the work and wrote the manuscript.

Corresponding author

Correspondence to Patrick Aloy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–3, Supplementary Tables 1, 2 and 4 (PDF 630 kb)

Supplementary Table 3

Structures used for the structural annotation of the Complement Cascade pathway (XLSX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mosca, R., Céol, A. & Aloy, P. Interactome3D: adding structural details to protein networks. Nat Methods 10, 47–53 (2013). https://doi.org/10.1038/nmeth.2289

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nmeth.2289

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing