Abstract
We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Uetz, P. et al. A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627 (2000).
Ito, T. et al. A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc. Natl. Acad. Sci. USA 98, 4569–4574 (2001).
Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).
Gavin, A.C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).
Giot, L. et al. A protein interaction map of Drosophila melanogaster. Science 302, 1727–1736 (2003).
Formstecher, E. et al. Protein interaction mapping: a Drosophila case study. Genome Res. 15, 376–384 (2005).
Stanyon, C.A. et al. A Drosophila protein-interaction map centered on cell-cycle regulators. Genome Biol. 5, R96 (2004).
Li, S. et al. A map of the interactome network of the metazoan C. elegans. Science 303, 540–543 (2004).
von Mering, C. et al. Comparative assessment of large-scale data sets of protein-protein interactions. Nature 417, 399–403 (2002).
Peri, S. et al. Development of human protein reference database as an initial platform for approaching systems biology in humans. Genome Res. 13, 2363–2371 (2003).
Bader, G.D., Betel, D. & Hogue, C.W. BIND: the Biomolecular Interaction Network Database. Nucleic Acids Res. 31, 248–250 (2003).
Salwinski, L. et al. The Database of Interacting Proteins: 2004 update. Nucleic Acids Res. 32, Database issue, D449–D451 (2004).
Pagel, P. et al. The MIPS mammalian protein-protein interaction database. Bioinformatics 21, 832–834 (2005).
Zanzoni, A. et al. MINT: a Molecular INTeraction database. FEBS Lett. 513, 135–140 (2002).
Hermjakob, H. et al. IntAct: an open source molecular interaction database. Nucleic Acids Res. 32, D452–D455 (2004).
Matthews, L.R. et al. Identification of potential interaction networks using sequence-based searches for conserved protein-protein interactions or “interologs”. Genome Res. 11, 2120–2126 (2001).
Sharan, R. et al. Conserved patterns of protein interaction in multiple species. Proc. Natl. Acad. Sci. USA 102, 1974–1979 (2005).
Guldener, U. et al. CYGD: the Comprehensive Yeast Genome Database. Nucleic Acids Res. 33, D364–D368 (2005).
O'Brien, K.P., Remm, M. & Sonnhammer, E.L. Inparanoid: a comprehensive database of eukaryotic orthologs. Nucleic Acids Res. 33, D476–D480 (2005).
Hazbun, T.R. & Fields, S. Networking proteins in yeast. Proc. Natl. Acad. Sci. USA 98, 4277–4278 (2001).
Legrain, P. & Selig, L. Genome-wide protein interaction maps using two-hybrid systems. FEBS Lett. 480, 32–36 (2000).
Mrowka, R., Patzak, A. & Herzel, H. Is there a bias in proteome research? Genome Res. 11, 1971–1973 (2001).
Wojcik, J., Boneca, I.G. & Legrain, P. Prediction, assessment and validation of protein interaction maps in bacteria. J. Mol. Biol. 323, 763–770 (2002).
Lehner, B. & Fraser, A.G. A first-draft human protein-interaction map. Genome Biol. 5, R63 (2004).
Sun, W. et al. Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization. Cancer Lett. 212, 83–93 (2004).
Zaza, G. et al. Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood 104, 1435–1441 (2004).
Shorter, J. et al. GRASP55, a second mammalian GRASP protein involved in the stacking of Golgi cisternae in a cell-free system. EMBO J. 18, 4949–4960 (1999).
Short, B. et al. A GRASP55-rab2 effector complex linking Golgi structure to membrane traffic. J. Cell Biol. 155, 877–883 (2001).
Kataoka, N., Diem, M.D., Kim, V.N., Yong, J. & Dreyfuss, G. Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon-exon junction complex. EMBO J. 20, 6424–6433 (2001).
Gorbea, C., Taillandier, D. & Rechsteiner, M. Mapping subunit contacts in the regulatory complex of the 26 S proteasome. S2 and S5b form a tetramer with ATPase subunits S4 and S7. J. Biol. Chem. 275, 875–882 (2000).
Ishizuka, T. et al. Human immunodeficiency virus type 1 Tat binding protein-1 is a transcriptional coactivator specific for TR. Mol. Endocrinol. 15, 1329–1343 (2001).
Richmond, C., Gorbea, C. & Rechsteiner, M. Specific interactions between ATPase subunits of the 26 S protease. J. Biol. Chem. 272, 13403–13411 (1997).
Fujiwara, T., Watanabe, T.K., Tanaka, K., Slaughter, C.A. & DeMartino, G.N. cDNA cloning of p42, a shared subunit of two proteasome regulatory proteins, reveals a novel member of the AAA protein family. FEBS Lett. 387, 184–188 (1996).
Haft, C.R., Klausner, R.D. & Taylor, S.I. Involvement of dileucine motifs in the internalization and degradation of the insulin receptor. J. Biol. Chem. 269, 26286–26294 (1994).
Scita, G. et al. EPS8 and E3B1 transduce signals from Ras to Rac. Nature 401, 290–293 (1999).
Jeong, H., Mason, S.P., Barabasi, A.L. & Oltvai, Z.N. Lethality and centrality in protein networks. Nature 411, 41–42 (2001).
Eppig, J.T. et al. The Mouse Genome Database (MGD): from genes to mice–a community resource for mouse biology. Nucleic Acids Res. 33, 471–475 (2005).
Hollander, M. & Wolfe, D.A. Nonparametric Statistical Inference 27–33 (John Wiley & Sons, New York, 1973).
Coulomb, S., Bauer, M., Bernard, D. & Marsolier-Kergoat, M.C. Gene essentiality and the topology of protein interaction networks. Proc. Biol. Sci. 272, 1721–1725 (2005).
Hamosh, A., Scott, A.F., Amberger, J.S., Bocchini, C.A. & McKusick, V.A. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 33, Database issue, D514–D517 (2005).
Arking, D.E., Chugh, S.S., Chakravarti, A. & Spooner, P.M. Genomics in sudden cardiac death. Circ. Res. 94, 712–723 (2004).
Albert, R. & Barabasi, A.L. Statistical mechanics of complex networks. Rev. Mod. Phys. 74, 47–97 (2002).
Breitkreutz, B.J., Stark, C. & Tyers, M. Osprey: a network visualization system. Genome Biol. 4, R22 (2003).
Cherry, J.M. et al. SGD: Saccharomyces Genome Database. Nucleic Acids Res. 26, 73–79 (1998).
Pandey, A. et al. Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain. Oncogene 21, 3939–3948 (2002).
Egan, J.P. Signal Detection Theory and ROC Analysis (Academic, New York, 1975).
Cox, D.R. & Snell, E.J. Analysis of Binary Data (Chapman and Hall, London, 1970).
Ihaka, R. & Gentleman, R.R. A language for data analysis and graphics. J. Comput. Graph. Statist. 5, 299–314 (1996).
Acknowledgements
A.P., J.D.B. and J.S.B. were supported by a grant from the National Institutes of Health (U54 RR020839). G.P. was supported by a grant from the National Science Foundation (NSF 034211), J.S.B. was supported by grants from the US National Institutes of Health (R41 GM073492 and R01 GM067761) and the Whitaker Foundation and S.P. was supported by the IZKF Würzburg project. The authors thank J. Eppig and C. Bult for providing knockout data from the Mouse Genome Database and B. Migeon, N. Katsanis and J. Mendell for helpful suggestions. The HPRD was developed with funding from the National Institutes of Health and the Institute of Bioinformatics.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The Human Protein Reference Database was developed with funding from the US National Institutes of Health and the Institute of Bioinformatics. A.P. serves as Chief Scientific Advisor to the Institute of Bioinformatics. A.P. is entitled to a share of the licensing fees paid to the Johns Hopkins University by commercial entities for use of the database. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
Supplementary information
Supplementary Fig. 1
Subclusters conserved between human and fly (PDF 216 kb)
Supplementary Fig. 2
Subclusters conserved between human and worm (PDF 231 kb)
Supplementary Fig. 3
Subclusters conserved between human and yeast (PDF 230 kb)
Supplementary Fig. 4
PPIs in essential versus non-essential genes (PDF 207 kb)
Supplementary Table 1
Overlap of worm and fly Y2H data with human protein-protein interactions. (PDF 109 kb)
Supplementary Table 2
Overlap of worm and fly interaction but not in humans (with corresponding orthologs in humans). (PDF 139 kb)
Rights and permissions
About this article
Cite this article
Gandhi, T., Zhong, J., Mathivanan, S. et al. Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet 38, 285–293 (2006). https://doi.org/10.1038/ng1747
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1747
This article is cited by
-
A novel candidate disease gene prioritization method using deep graph convolutional networks and semi-supervised learning
BMC Bioinformatics (2022)
-
ImitateDB: A database for domain and motif mimicry incorporating host and pathogen protein interactions
Amino Acids (2022)
-
Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression
Molecular Psychiatry (2021)
-
A dual controllability analysis of influenza virus-host protein-protein interaction networks for antiviral drug target discovery
BMC Bioinformatics (2019)
-
Network-based prediction of protein interactions
Nature Communications (2019)