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The BioPlex Network: A Systematic Exploration of the Human Interactome
Open accessAbstract
Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors.
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“It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93.”
From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [19]
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In the citing paper
“The CCC complex comprises twelve components, the coiled coil domain-containing proteins CCDC22 and CCDC93 and ten COMMD (copper metabolism MURR1 [Mouse U2af1-rs1 region 1) domain) family members COMMD1-COMMD10.2,16,17,18,19”
From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [19]
Experimental — accuracy not yet measuredIn the citing paper
“The community detection approach was well illustrated in recent analyses of protein-protein interaction networks in yeast (Dutkowski et al., 2013) and human (Huttlin et al., 2015).”
From Mapping the multiscale structure of biological systems (2021) · cites this paper as Huttlin et al., 2015
In the citing paper
“In the human study, the authors first performed clique percolation to determine high-level protein communities; subsequently, they ran modularity-based clustering to further subdivide these communities into more granular subsystems, resulting in a multi-layer hierarchical structure (Figure 3A).”
From Mapping the multiscale structure of biological systems (2021) · cites this paper as Huttlin et al., 2015
In the citing paper
“several high throughput studies using robust affinity purification-mass spectrometry methodologies to elucidate protein interaction networks have revealed the interaction of ABCD1 with AT2B2 [ 167 ] and ABCD3 with AT2B2 and AT2A2 [ 168 , 169 ]”
From Peroxisomal ABC Transporters: An Update (2021) · cites this paper as [169]
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A learned embedding for efficient joint analysis of millions of mass spectra
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UBB pseudogene 4 encodes functional ubiquitin variants
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“These are 77% similar by sequence and share 80% of interactors (Huttlin et al., 2015), so they can be considered together.”
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“The MitoCatalase sequence was cloned into the pPHAGE C-TAP vector (Huttlin et al., 2015).”
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“VAPs have a large interactome, including kinases, vesicle trafficking proteins, kinesins, AKAPs and lipid transfer proteins [65,71], all of which may play important roles at Kv2-induced ER/PM junctions.”
BackgroundHarris, V. M., Koelsch, K. A., Kurien, B. T., Harley, I. T. W., Wren, J. D., Harley, J. B., & Scofield, R. H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02160 · Cited by 52
“Further evidence supporting a role for CXorf21 in innate immunity and in the pathogenesis of SLE and pSS come fromThe BioPlex Network, a publicly-available, unbiased protein-protein interaction screening project (17).”
BackgroundCapturing dynamic protein interactions
Li, X., Chavali, P. L., & Babu, M. M. (2018) · Science · doi:10.1126/science.aat0576 · Cited by 52
Mapping protein–protein interactions by mass spectrometry
Liu, X., Abad, L., Chatterjee, L., Cristea, I. M., & Varjosalo, M. T. (2024) · Mass Spectrometry Reviews · doi:10.1002/mas.21887 · Cited by 54
“The BioPlex Network has made significant contributions through high ‐ throughput AP ‐ MS. BioPlex 1.0 (Huttlin et al., 2015) laid the foundation of the human protein ‐ protein interaction network by screening thousands of PPIs.”
InfluentialZaslavsky, B. Y., Uversky, V. N., & Chait, A. (2016) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2016.02.017 · Cited by 53
“Protein based interactions are recognized as fundamental for organization and regulation of essentially all biological processes, and some of these interactions are commonly changed under pathological conditions [252].”
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Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21
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Poly(ADP-ribose)-dependent ubiquitination and its clinical implications
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BackgroundInfluentialProgress and challenges in mass spectrometry-based analysis of antibody repertoires
Snapkov, I., Chernigovskaya, M., Sinitcyn, P. G., Quý, K. L., Nyman, T. A., & Greiff, V. (2021) · Trends in biotechnology · doi:10.1016/j.tibtech.2021.08.006 · Cited by 56
New insights into the gene expression associated to amyotrophic lateral sclerosis
Recabarren-Leiva, D., & Alarcón, M. A. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.12.016 · Cited by 49
Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death
Douglas, T., & Saleh, M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.014 · Cited by 49
Protein maps chart the causes of disease
Fessenden, M. (2017) · Nature · doi:10.1038/549293a · Cited by 49
The IQGAP scaffolds: Critical nodes bridging receptor activation to cellular signaling
Thines, L., Roushar, F. J., Hedman, A. C., & Sacks, D. B. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202205062 · Cited by 49
Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
Luo, Z., Huang, Y., Batra, N., Chen, Y., Huang, H., Wang, Y., Zhang, Z., Li, S., Chen, C., Wang, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44572-6 · Cited by 51
“SearchingofiRhom1-interactivepartnersinproteomicdatabase 22,23 identi fi ed MAPK14 as one potential candidate that is regulated by iRhom1 through protein-protein interaction (PPI).”
Global Deletion of TSPO Does Not Affect the Viability and Gene Expression Profile
Wang, H., Zhai, K., Xue, Y., Yang, J. Y., Yang, Q., Fu, Y., Hu, Y., Liu, F., Wang, W., Cui, L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167307 · Cited by 52
Huang, H., Zheng, J., Shen, N., Wang, G., Zhou, G., Fang, Y., Lin, J., & Zhao, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-28280-6 · Cited by 49
Wesdorp, M., Murillo‐Cuesta, S., Peters, T. A., Celaya, A. M., Oonk, A. M. M., Schraders, M., Oostrik, J., Gómez-Rosas, E., Beynon, A. J., Hartel, B. P., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.05.011 · Cited by 49
“Interestingly, an association of MPZL2 and occludin has been observed in a highthroughput human protein interaction study.(69) Occludin is a tight-junction (TJ) protein essential for functional integrity of the reticular lamina of the organ of Corti.”
BackgroundPaik, Y., Lane, L., Kawamura, T., Chen, Y., Cho, J., LaBaer, J., Yoo, J. S., Domont, G. B., Corrales, F. J., Omenn, G. S., et al. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00383 · Cited by 48
Genetic variations on SETD5 underlying autistic conditions
Fernandes, I. R., da Cruz, A. C. P., Ferrasa, A., Phan, D., Herai, R. H., & Muotri, A. R. (2018) · Developmental Neurobiology · doi:10.1002/dneu.22584 · Cited by 50
Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95
Sharma, S., Carmona, A. L., Skowronek, A., Yu, F., Collins, M. O., Naik, S., Murzeau, C. M., Tseng, P.-L., & Erdmann, K. S. (2019) · Nature Communications · doi:10.1038/s41467-019-11025-y · Cited by 50
Accessory proteins of the zDHHC family of S-acylation enzymes
Salaün, C., Locatelli, C., Zmuda, F., González, J. C., & Chamberlain, L. H. (2020) · Journal of Cell Science · doi:10.1242/jcs.251819 · Cited by 49
Zaykov, V., & Chaqour, B. (2021) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-021-00650-2 · Cited by 48
Structure and interactions of the endogenous human Commander complex
Laulumaa, S., Kumpula, E.-P., Huiskonen, J. T., & Varjosalo, M. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01246-1 · Cited by 46
“7, 20), and a DENN (differentially expressed in normal and neoplastic cells) domain-containing protein 10 (DENND10) 4,21 .”
Standard Proteoforms and Their Complexes for Native Mass Spectrometry
Schachner, L. F., Ives, A. N., McGee, J. P., Melani, R. D., Kafader, J. O., Compton, P. D., Patrie, S. M., & Kelleher, N. L. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02191-w · Cited by 48
“Also, data processing and bioinformatics resources now permit the precise MS deconvolution of high mass assemblies (e.g., protein deconvolution, MagTran, UniDec) [26, 27], omics-level prediction of MPCs [16, 28], and the automated interpretation of tandem MS data (e.g., ProSight Lite, ProSightPC, TDValidator, mMass) […”
InfluentialCharacterization of a novel RP2–OSTF1 interaction and its implication for actin remodelling
Lyraki, R., Lokaj, M., Soares, D. C., Little, A., Vermeren, M., Marsh, J. A., Wittinghofer, A., & Hurd, T. W. (2018) · Journal of Cell Science · doi:10.1242/jcs.211748 · Cited by 47
“Subsequent to our discovery, the interaction was recently identified in a large-scale study of the human interactome, further validating the interaction (Huttlin et al., 2015).”
BackgroundThe Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis
Borgese, N., Iacomino, N., Colombo, S. F., & Navone, F. (2021) · Cells · doi:10.3390/cells10081865 · Cited by 47
Su, C., Hou, Y., Xu, J., Xu, Z., Zhou, M., Ke, A., Li, H., Xu, J., Brendel, M., Maasch, J. R. M. A., et al. (2024) · npj Digital Medicine · doi:10.1038/s41746-024-01175-9 · Cited by 56
“0 110 ; (v) signaling networks by literature-derived low-throughput experiments from the SignaLink2.”
Li, H., Chen, Y.-F., Feng, W. M., Cai, H., Mei, Y., Jiang, Y., Chen, T., Xu, K., & Feng, D.-X. (2016) · Gene · doi:10.1016/j.gene.2016.11.046 · Cited by 48
CEP19 cooperates with FOP and CEP350 to drive early steps in the ciliogenesis programme
Mojarad, B. A., Gupta, G. D., Hasegan, M., Goundiam, O., Basto, R., Gingras, A., & Pelletier, L. (2017) · Open Biology · doi:10.1098/rsob.170114 · Cited by 48
van Tran, N., Muller, L., Ross, R. L., Lestini, R., Létoquart, J., Ulryck, N., Limbach, P. A., de Crécy‐Lagard, V., Cianférani, S., & Graille, M. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky638 · Cited by 48
“Hence, precise understanding of molecular details ruling the association of a single protein with various proteins adopting the same fold but exhibiting low sequence identity is of importance to decipher the numerous interaction networks that contribute to most cellular pathways (89,90).”
BackgroundER-Mitochondria Calcium Transfer, Organelle Contacts and Neurodegenerative Diseases
Vallese, F., Barazzuol, L., Maso, L., Brini, M., & Calí, T. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12457-1_29 · Cited by 48
Farhan, S. M. K., Nixon, K. C. J., Everest, M., Edwards, T. N., Long, S., Segal, D., Knip, M. J., Arts, H. H., Chakrabarti, R., Wang, J., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx316 · Cited by 43
Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Harvey, L. D., Alotaibi, M., Tai, Y., Tang, Y., Kim, H. J., Kelly, N. J., Sun, W., Woodcock, C.-S. C., Arshad, S., Culley, M. K., et al. (2025) · Science · doi:10.1126/science.adn7277 · Cited by 56
Mukherjee, I., Roy, S., & Chakrabarti, S. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00023 · Cited by 49
SERPINA3 is a key modulator of HNRNP-K transcriptional activity against oxidative stress in HCC
Ko, E., Kim, J.-S., Bae, J. W., Kim, J., Park, S.-G., & Jung, G. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101217 · Cited by 39
Network integration of multi-tumour omics data suggests novel targeting strategies
do Valle, Í. F., Menichetti, G., Simonetti, G., Bruno, S., Zironi, I., Durso, D. F., Mombach, J. C. M., Martinelli, G., Castellani, G., & Remondini, D. (2018) · Nature Communications · doi:10.1038/s41467-018-06992-7 · Cited by 48
Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain
Chantranupong, L., Saulnier, J. L., Wang, W., Jones, D. R., Pacold, M. E., & Sabatini, B. L. (2020) · eLife · doi:10.7554/elife.59699 · Cited by 41
Chromosomal instability by mutations in the novel minor spliceosome component CENATAC
de Wolf, B., Oghabian, A., Akinyi, M. V., Hanks, S., Tromer, E. C., van Hooff, J. J. E., van Voorthuijsen, L., van Rooijen, L. E., Verbeeren, J., Uijttewaal, E. C. H., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106536 · Cited by 45
“As predicted by our co-evolution analysis and in agreement with a previous high-throughput screen (Hart et al, 2015; Hein et al, 2015; Huttlin et al, 2015, 2017), mass spectrometry analysis of proteins co-purifying with CENATAC identified several known spliceosome components that are shared by both…”
Rab39 and its effector UACA regulate basolateral exosome release from polarized epithelial cells
Matsui, T., Sakamaki, Y., Nakashima, S., & Fukuda, M. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110875 · Cited by 47
Xiong, D., Qiu, Y., Zhao, J., Zhou, Y., Lee, D., Gupta, S., Torres, M., Lü, W., Liang, S., Kang, J. J., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02428-4 · Cited by 49
“Extensive efforts have been dedicated both experimentally (such as HuRI 99 , BioPlex 100 and OpenCell 101 ) and computationally (such as PrePPI 102 and HIGH-PPI 103 ) to ascertaining which pairs of human proteins interact.”
Zeng, H., Yu, M., Tan, H., Li, Y., Su, W., Shi, H., Dhungana, Y., Guy, C. S., Neale, G. A. M., Cloer, C., et al. (2018) · Science Advances · doi:10.1126/sciadv.aar5701 · Cited by 48
“The PPI database was constructed by merging the STRING PPI database (version 10) (94) with the affinity purification–MS–based BioPlex PPI database (using the latest version of June 2015) (95).”
MethodStructural insights into the architecture and membrane interactions of the conserved COMMD proteins
Healy, M. D., Hospenthal, M. K., Hall, R. J., Chandra, M., Chilton, M., Tillu, V., Chen, K.-E., Celligoi, D. J., McDonald, F. J., Cullen, P. J., et al. (2018) · eLife · doi:10.7554/elife.35898 · Cited by 50
Nizon, M., Laugel, V., Flanigan, K. M., Pastore, M., Waldrop, M. A., Rosenfeld, J. A., Marom, R., Xiao, R., Gerard, A., Pichon, O., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0557-3 · Cited by 46
James, C., Müller, M., Goldberg, M. W., Lenz, C., Urlaub, H., & Kehlenbach, R. H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007283 · Cited by 45
“In total, 100 proteins have been reported to directly or indirectly interact with VAPB and/or the highly similar protein VAPA (10, 11) (see also https://thebiogrid.”
BackgroundInfluentialPortillo, F., Vázquez, J., & Pajares, M. A. (2020) · Biochimie · doi:10.1016/j.biochi.2020.02.015 · Cited by 47
“The functional relevance of most of these interactions has not been studied, except for the AHCYAHCYL1 interaction (Fig.”
BackgroundMethodInfluentialRosenberger, G., Heusel, M., Bludau, I., Collins, B. C., Martelli, C., Williams, E. G., Xue, P., Liu, Y., Aebersold, R. H., & Califano, A. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.006 · Cited by 40
Ubiquitin-dependent remodeling of the actin cytoskeleton drives cell fusion
Rodríguez-Pérez, F., Manford, A. G., Pogson, A. N., Ingersoll, A. J., Martínez-González, B., & Rapé, M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.01.016 · Cited by 48
“Unique proteins were identified by comparing each IP to a dataset of 40-150 similar (unique databases for C2C12) aFLAG IP/mass spectrometry samples using CompPASS analysis by using the R specific package ComPASS (Huttlin et al., 2015).”
MethodA Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases
Zolotareva, O., & Kleine, M. (2019) · Journal of Integrative Bioinformatics · doi:10.1515/jib-2018-0069 · Cited by 46
Yadollahi, P., Jeon, Y., Ng, W. L., & Choi, I. (2021) · BMB Reports · doi:10.5483/bmbrep.2021.54.1.241 · Cited by 46
“ATM, ATR, PDS5B, and TTL1, and kinases involved in survival and anchorage-independent cell growth (75, 76).”
BackgroundVAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity
Bapat, O., Purimetla, T., Krüssel, S., Shah, M., Fan, R., Thum, C., Rupprecht, F., Langer, J. D., & Rangaraju, V. (2024) · Nature Communications · doi:10.1038/s41467-023-44233-8 · Cited by 44
“VAP is identi fi ed as an actin interactor in the BioGRID database 34 based on human interactome network analysis studies 51,52 .”
Multimodal cell maps as a foundation for structural and functional genomics
Schaffer, L. V., Hu, M., Qian, G., Moon, K., Pal, A., Soni, N., Latham, A. P., Vaites, L. P., Tsai, D., Mattson, N. M., et al. (2025) · Nature · doi:10.1038/s41586-025-08878-3 · Cited by 48
“Overall, SEC data validated 89 assemblies (5% false-discovery rate (FDR)), corresponding to 43% of assemblies (76 out of 175) with more than 5 proteins and 61% of assemblies (59 out of 96) with more than 15 proteins (Fig.”
Influential
Metadata
- Authors
- Huttlin, E. L., Ting, L., Bruckner, R. J., Gebreab, F., Gygi, M. P., Szpyt, J., Tam, S., Zarraga, G., Colby, G., Baltier, K., Dong, R., Guarani, V., Vaites, L. P., Ordureau, A., Rad, R., Erickson, B. K., Wühr, M., Chick, J., Zhai, B., Kolippakkam, D., Mintseris, J., Obar, R. A., Harris, T., Artavanis-Tsakonas, S., Sowa, M. E., De Camilli, P., Paulo, J. A., Harper, J. W., & Gygi, S. P.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Biogen (United States) (US)
- Corresponding author
- Harper, J. Wade
- Gygi, Steven P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 2
- Pages
- 425-440
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4617211
- OpenAlex
- W1611787727
- Cited by
- 1,425
- References
- 41
- Citations by year
- 2026: 46 · 2025: 82 · 2024: 116 · 2023: 105 · 2022: 98 · 2021: 162 · 2020: 159 · 2019: 197 · 2018: 171 · 2017: 147 · 2016: 122 · 2015: 18
- FWCI
- 66.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation
- Biogen
- Charles A. King Trust
- National Institutes of Health (HG006673)
- National Human Genome Research Institute (U41HG006673)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK098285)
- National Institute of Neurological Disorders and Stroke (R37NS036251)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- BioPlex, human interactome, protein-protein interaction, protein complexes, protein domain interactions, community structure, HEK293T cells, VAPB, amyotrophic lateral sclerosis
- MeSH terms
- Amyotrophic Lateral Sclerosis, Humans, Proteins, Mass Spectrometry, Protein Interaction Mapping, Proteomics, Protein Interaction Maps
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