A Proteome-scale Map of the Human Interactome Network

Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ?30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a "broader" human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help "connect the dots" of the genomic revolution.

Citing Articles

A quantitative intracellular peptide-binding assay reveals recognition determinants and context dependence of short linear motifs.

Subbanna M, Winters M, Ord M, Davey N, Pryciak P J Biol Chem. 2025; 301(3):108225.

PMID: 39864625 PMC: 11879687. DOI: 10.1016/j.jbc.2025.108225.

Predicting drug combination side effects based on a metapath-based heterogeneous graph neural network.

Tian L, Wang Q, Zhou Z, Liu X, Zhang M, Yan G BMC Bioinformatics. 2025; 26(1):16.

PMID: 39815175 PMC: 11734363. DOI: 10.1186/s12859-024-06028-6.

ICoN: integration using co-attention across biological networks.

Tasnina N, Murali T Bioinform Adv. 2025; 5(1):vbae182.

PMID: 39801779 PMC: 11723530. DOI: 10.1093/bioadv/vbae182.

Beyond Misfolding: A New Paradigm for the Relationship Between Protein Folding and Aggregation.

Choi S, Jin Y, Choi Y, Seong B Int J Mol Sci. 2025; 26(1.

PMID: 39795912 PMC: 11720324. DOI: 10.3390/ijms26010053.

Cortex-Specific Deficiency Induces Defects in Cortical Neuron Development and Autism-Like Behaviors in Mice.

Wang J, Zhang J, Li J, Gao Q, Chen J, Jia C J Neurosci. 2025; 45(9).

PMID: 39779369 PMC: 11867004. DOI: 10.1523/JNEUROSCI.1072-24.2024.

References

Eyckerman S, Verhee A, der Heyden J, Lemmens I, Ostade X, Vandekerckhove J . Design and application of a cytokine-receptor-based interaction trap. Nat Cell Biol. 2002; 3(12):1114-9. DOI: 10.1038/ncb1201-1114. View

Kerrien S, Aranda B, Breuza L, Bridge A, Broackes-Carter F, Chen C . The IntAct molecular interaction database in 2012. Nucleic Acids Res. 2011; 40(Database issue):D841-6. PMC: 3245075. DOI: 10.1093/nar/gkr1088. View

Hornbeck P, Kornhauser J, Tkachev S, Zhang B, Skrzypek E, Murray B . PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 2011; 40(Database issue):D261-70. PMC: 3245126. DOI: 10.1093/nar/gkr1122. View

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

Mann K, Ward J, Yew C, Kovochich A, Dawson D, Black M . Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A. 2012; 109(16):5934-41. PMC: 3341075. DOI: 10.1073/pnas.1202490109. View

Rozenblatt-Rosen O, Deo R, Padi M, Adelmant G, Calderwood M, Rolland T . Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature. 2012; 487(7408):491-5. PMC: 3408847. DOI: 10.1038/nature11288. View

Havugimana P, Hart G, Nepusz T, Yang H, Turinsky A, Li Z . A census of human soluble protein complexes. Cell. 2012; 150(5):1068-81. PMC: 3477804. DOI: 10.1016/j.cell.2012.08.011. View

Zhang Q, Petrey D, Deng L, Qiang L, Shi Y, Aye Thu C . Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature. 2012; 490(7421):556-60. PMC: 3482288. DOI: 10.1038/nature11503. View

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

10.

Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B . Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012; 44(12):1316-20. DOI: 10.1038/ng.2469. View

11.

Chatr-Aryamontri A, Breitkreutz B, Heinicke S, Boucher L, Winter A, Stark C . The BioGRID interaction database: 2013 update. Nucleic Acids Res. 2012; 41(Database issue):D816-23. PMC: 3531226. DOI: 10.1093/nar/gks1158. View

12.

Caufield J, Sakhawalkar N, Uetz P . A comparison and optimization of yeast two-hybrid systems. Methods. 2012; 58(4):317-24. PMC: 5737776. DOI: 10.1016/j.ymeth.2012.12.001. View

13.

Vogelstein B, Papadopoulos N, Velculescu V, Zhou S, Diaz Jr L, Kinzler K . Cancer genome landscapes. Science. 2013; 339(6127):1546-58. PMC: 3749880. DOI: 10.1126/science.1235122. View

14.

Lawrence M, Stojanov P, Mermel C, Robinson J, Garraway L, Golub T . Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014; 505(7484):495-501. PMC: 4048962. DOI: 10.1038/nature12912. View

15.

Stenson P, Mort M, Ball E, Shaw K, Phillips A, Cooper D . The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2013; 133(1):1-9. PMC: 3898141. DOI: 10.1007/s00439-013-1358-4. View

16.

Woodsmith J, Stelzl U . Studying post-translational modifications with protein interaction networks. Curr Opin Struct Biol. 2014; 24:34-44. DOI: 10.1016/j.sbi.2013.11.009. View

17.

Kim M, Pinto S, Getnet D, Nirujogi R, Manda S, Chaerkady R . A draft map of the human proteome. Nature. 2014; 509(7502):575-81. PMC: 4403737. DOI: 10.1038/nature13302. View

18.

Wilhelm M, Schlegl J, Hahne H, Gholami A, Lieberenz M, Savitski M . Mass-spectrometry-based draft of the human proteome. Nature. 2014; 509(7502):582-7. DOI: 10.1038/nature13319. View

19.

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

20.

Copeland N, Jenkins N . Harnessing transposons for cancer gene discovery. Nat Rev Cancer. 2010; 10(10):696-706. DOI: 10.1038/nrc2916. View