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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The community detection approach was well illustrated in recent analyses of protein-protein interaction networks in yeast and human.
“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 human protein interaction study, clique percolation determined high-level protein communities, and modularity-based clustering subdivided them into more granular subsystems, resulting in a multi-layer hierarchical structure.
“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
Several high throughput studies using robust affinity purification-mass spectrometry methodologies revealed interaction of ABCD1 with AT2B2 and ABCD3 with AT2B2 and AT2A2.
“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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InfluentialAnalysis of the Human Endogenous Coregulator Complexome
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“A composite protein-protein interaction (PPI) network was built by combining STRING (v10) (Szklarczyk et al., 2015), BioPlex (Huttlin et al., 2015), and InWeb (Hopkins et al., 2017), as well as three unbiased SG interactomes (Jain et al., 2016; Markmiller et al., 2018; Youn et al., 2018).”
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“Localization predictions were performed as described previously (Huttlin et al., 2015).”
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“Since the advent of high-throughput approaches to detect protein (1– 3) and genetic interactions (4), the depth of coverage and accuracy of biological interaction networks has continued to improve (5,6), with increased resolution at the level of protein isoforms (7) and metabolites (8,9).”
BackgroundMethodContext-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules
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AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs
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The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
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“To identify potential GATOR2binding partners, we interrogated BioPlex, a database of human protein-protein interactions generated from immunoprecipitation followed by mass spectrometry of 2,594 proteins stably expressed in HEK293T cells (Huttlin et al., 2015).”
InfluentialSelf-citationP-Body Purification Reveals the Condensation of Repressed mRNA Regulons
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“4 Molecular Cell 68, 1–14, October 5, 2017 right) (Hein et al., 2015; Huttlin et al., 2015).”
MethodMassive mining of publicly available RNA-seq data from human and mouse
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“This is likely because a part of BioPLEX is contained within hu.”
MethodInfluentialComparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms
Gordon, D. E., Hiatt, J. B., Bouhaddou, M., Rezelj, V. V., Ulferts, S., Braberg, H., Jureka, A. S., Obernier, K., Guo, J. Z., Batra, J., et al. (2020) · Science · doi:10.1126/science.abe9403 · Cited by 731 · see citing works
CORUM: the comprehensive resource of mammalian protein complexes—2019
Giurgiu, M., Reinhard, J., Brauner, B., Dunger-Kaltenbach, I., Fobo, G., Frishman, G., Montrone, C., & Ruepp, A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky973 · Cited by 595 · see citing works
Native Mass Spectrometry: What is in the Name?
Leney, A. C., & Heck, A. J. R. (2017) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-016-1545-3 · Cited by 602 · see citing works
“Mass spectrometry (MS), specifically MS-based proteomics, has already played a pivotal role in deciphering the many protein complexes and protein interaction networks that are present in the cell, typically at the end of a pipe-line that starts with the immune-purification of a tagged-bait protein, followed by identif…”
BackgroundMethodA scored human protein–protein interaction network to catalyze genomic interpretation
Li, T., Wernersson, R., Hansen, R. B., Horn, H., Mercer, J., Slodkowicz, G., Workman, C. T., Rigina, O., Rapacki, K., Stærfeldt, H., et al. (2016) · Nature Methods · doi:10.1038/nmeth.4083 · Cited by 630 · see citing works
Accessory subunits are integral for assembly and function of human mitochondrial complex I
Stroud, D. A., Surgenor, E. E., Formosa, L. E., Reljić, B., Frazier, A. E., Dibley, M. G., Osellame, L. D., Stait, T. L., Beilharz, T. H., Thorburn, D. R., et al. (2016) · Nature · doi:10.1038/nature19754 · Cited by 605 · see citing works
Regulation by 3′-Untranslated Regions
Mayr, C. (2017) · Annual Review of Genetics · doi:10.1146/annurev-genet-120116-024704 · Cited by 588 · see citing works
“This is illustrated in experiments studying PPIs by the use of constructs that contain only the coding regions (54).”
MethodBruderer, R., Bernhardt, O. M., Gandhi, T., Xuan, Y., Sondermann, J. R., Schmidt, M., Gómez‐Varela, D., & Reiter, L. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000314 · Cited by 479 · see citing works
Protein Aggregation Capture on Microparticles Enables Multipurpose Proteomics Sample Preparation*
Batth, T. S., Tollenaere, M. A. X., Rüther, P. L., González-Franquesa, A., Prabhakar, B. S., Bekker‐Jensen, S., Deshmukh, A. S., & Olsen, J. V. (2019) · Molecular & Cellular Proteomics · doi:10.1074/mcp.tir118.001270 · Cited by 448 · see citing works
There's Something Wrong with my MAM; the ER–Mitochondria Axis and Neurodegenerative Diseases
Paillusson, S., Stoica, R., Gomez-Suaga, P., Lau, D. H. W., Mueller, S., Miller, T., & Miller, C. C. J. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.01.008 · Cited by 439 · see citing works
“Recently, the biochemical interaction between VAPB and PTPIP51 was independently verified [49].”
BackgroundDefining the consequences of genetic variation on a proteome-wide scale
Chick, J. M., Munger, S. C., Simecek, P., Huttlin, E. L., Choi, K., Gatti, D. M., Raghupathy, N., Svenson, K. L., Churchill, G. A., & Gygi, S. P. (2016) · Nature · doi:10.1038/nature18270 · Cited by 361 · see citing works
Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation
Mitrea, D. M., Cika, J., Stanley, C., Nourse, A., Onuchic, P. L., Banerjee, P. R., Phillips, A. H., Park, C., Deniz, A., & Kriwacki, R. (2018) · Nature Communications · doi:10.1038/s41467-018-03255-3 · Cited by 379 · see citing works
“NPM1 is a multifunctional protein, which interacts with over 130 proteins 26 , many of them annotated to be localized within the nucleolus and shown to display multivalent R-motifs 13 .”
The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy
Gómez‐Suaga, P., Paillusson, S., Stoica, R., Noble, W. J., Hanger, D. P., & Miller, C. C. J. (2017) · Current Biology · doi:10.1016/j.cub.2016.12.038 · Cited by 413 · see citing works
A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging
Xiao, H., Jedrychowski, M. P., Schweppe, D. K., Huttlin, E. L., Yu, Q., Heppner, D. E., Li, J., Long, J., Mills, E. L., Szpyt, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.012 · Cited by 399 · see citing works
“Affinity purification experiments—Stable cell lines expressing C-terminally FLAGHA-tagged RARS, QARS, and GFP were created according to protocols described previously (Huttlin et al., 2015).”
Programmed death ligand 1 signals in cancer cells
Kornepati, A. V. R., Vadlamudi, R. K., & Curiel, T. J. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00431-4 · Cited by 398 · see citing works
Gordon, D. E., Jang, G. Μ., Bouhaddou, M., Xu, J., Obernier, K., O’Meara, M. J., Guo, J. Z., Swaney, D. L., Tummino, T. A., Hüttenhain, R., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.22.002386 · Cited by 419 · see citing works
Dong, R., Saheki, Y., Swarup, S., Lucast, L. J., Harper, J. W., & Camilli, P. V. D. (2016) · Cell · doi:10.1016/j.cell.2016.06.037 · Cited by 388 · see citing works
“Inspection of a high-throughput VAP interactome (Huttlin et al., 2015) revealed as one of the top hits SNX2, a component of the membrane deformation subcomplex of the retromer (Bonifacino and Rojas, 2006).”
Click Chemistry in Proteomic Investigations
Parker, C. G., & Pratt, M. R. (2020) · Cell · doi:10.1016/j.cell.2020.01.025 · Cited by 386 · see citing works
“Significant advances in enrichment techniques, ionization methods and instrument resolution have greatly facilitated the identification, characterization and quantitation of PTMs, while herculean proteomic studies have mapped networks rich with thousands of new candidate protein-protein interactions (PPIs) (Hein et al…”
Paillusson, S., Gómez‐Suaga, P., Stoica, R., Little, D., Gissen, P., Devine, M. J., Noble, W. J., Hanger, D. P., & Miller, C. C. J. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1704-z · Cited by 369 · see citing works
“Recently, the integral ER protein VAPB was shown to bind to the outer mitochondrial membrane protein PTPIP51 to form at least some of these tethers [20, 26, 40, 78, 79].”
Target identification among known drugs by deep learning from heterogeneous networks
Zeng, X., Zhu, S., Lu, W., Liu, Z., Huang, J., Zhou, Y., Fang, J., Huang, Y., Guo, H., Li, L., et al. (2020) · Chemical Science · doi:10.1039/c9sc04336e · Cited by 357 · see citing works
Mohammed, H., Taylor, C., Brown, G. D., Papachristou, E., Carroll, J., & D'Santos, C. (2016) · Nature Protocols · doi:10.1038/nprot.2016.020 · Cited by 316 · see citing works
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“Web server-based software such as Panther (37), GOrilla (38), DAVID (39), Bioplex (40), and KeGG (41) allowed us to extract biological information from the collected data.”
MethodSystematic Evaluation of Molecular Networks for Discovery of Disease Genes
Huang, J. K., Carlin, D. E., Yu, M. K., Zhang, W., Kreisberg, J. F., Tamayo, P., & Ideker, T. (2018) · Cell Systems · doi:10.1016/j.cels.2018.03.001 · Cited by 289 · see citing works
Regulation of the Hippo Pathway Transcription Factor TEAD
Lin, K. C., Park, H. W., & Guan, K. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.09.003 · Cited by 334 · see citing works
“However, human interactome studies show interaction between TEADs, suggesting that homo- and hetero- complexes may differentially regulate TEAD transcriptional activity [31, 32].”
BackgroundMurphy, S. E., & Levine, T. P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.02.009 · Cited by 325 · see citing works
Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control
Yau, R. G., Dörner, K., Castellanos, E. R., Haakonsen, D. L., Werner, A. A., Wang, N., Yang, X. W., Martinez-Martín, N., Matsumoto, M. L., Dixit, V. M., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.040 · Cited by 315 · see citing works
“In addition, mitotic regulators are often incorporated into stable complexes (Huttlin et al., 2015), and misfolded proteins rapidly engage in oligomeric interactions en route to aggregation (Bemporad and Chiti, 2012).”
Proteomic and interactomic insights into the molecular basis of cell functional diversity
Bludau, I., & Aebersold, R. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0231-2 · Cited by 297 · see citing works
The intracellular signalosome of PD-L1 in cancer cells
Escors, D., Gato, M., Zuazo, M., Arasanz, H., García-Granda, M. J., Vera, R., & Kochan, G. T. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0022-9 · Cited by 299 · see citing works
VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis.
Hua, R., Cheng, D., Coyaud, É., Freeman, S., Di Pietro, E., Wang, Y., Vissa, A., Yip, C. M., Fairn, G. D., Braverman, N., et al. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201608128 · Cited by 279 · see citing works
“In the screen, we only found ACBD5 to contain an FFAT domain (Huttlin et al., 2015).”
BackgroundQuantitative proteomics: challenges and opportunities in basic and applied research
Schubert, O. T., Röst, H. L., Collins, B. C., Rosenberger, G., & Aebersold, R. H. (2017) · Nature Protocols · doi:10.1038/nprot.2017.040 · Cited by 276 · see citing works
An Atomic Structure of the Human Spliceosome
Zhang, X., Yan, C., Hang, J., Finci, L. I., Lei, J., & Shi, Y. (2017) · Cell · doi:10.1016/j.cell.2017.04.033 · Cited by 268 · see citing works
“The C-terminal portion of PRKRIP1 binds the U2 snRNP (Huttlin et al., 2015), with the C-terminal five turns of the a helix placed in the major groove of the U2 snRNA duplex.”
Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function
Floyd, B. J., Wilkerson, E., Veling, M. T., Minogue, C. E., Xia, C., Beebe, E. T., Wrobel, R. L., Cho, H., Kremer, L. S., Alston, C. L., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.06.033 · Cited by 260 · see citing works
“Hosp et al., 2015; Huttlin et al., 2015; Keilhauer et al., 2015) have improved the ability to accurately detect PPIs, enabling researchers to overcome the systematic bias against poorly characterized proteins inherent in many large-scale ‘‘interactome’’ analyses (Sahni et al., 2015).”
ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER
Costello, J. L., Castro, I. G., Hacker, C., Schrader, T. A., Metz, J., Zeuschner, D., Azadi, A. S., Godinho, L. F., Costina, V., Findeisen, P., et al. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201607055 · Cited by 251 · see citing works
“Additionally, in a genome-wide protein interaction screen, ACBD5 was among proteins identified as potential VAPB interaction partners (Huttlin et al., 2015).”
Dihydroxyacetone phosphate signals glucose availability to mTORC1
Orozco, J. M., Krawczyk, P. A., Scaria, S. M., Cangelosi, A. L., Chan, S. H., Kunchok, T., Lewis, C. A., & Sabatini, D. M. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0250-5 · Cited by 245 · see citing works
Thermal proximity coaggregation for system-wide profiling of protein complex dynamics in cells
Tan, C. S. H., Go, K. D., Bisteau, X., Dai, L., Yong, C. H., Prabhu, N., Ozturk, M. B., Lim, Y. T., Sreekumar, L., Lengqvist, J., et al. (2018) · Science · doi:10.1126/science.aan0346 · Cited by 224 · see citing works
The diverse and expanding role of mass spectrometry in structural and molecular biology
Lössl, P., van de Waterbeemd, M., & Heck, A. J. (2016) · The EMBO Journal · doi:10.15252/embj.201694818 · Cited by 222 · see citing works
“…et al , 2013; Lee et al , 2015), public data repositories (Perez-Riverol et al , 2015), and tools to define and study protein interaction and signaling networks (Gavin et al , 2002; Hein et al , 2015; Huttlin et al , 2015) allow translating MS data into sound and meaningful biological information.”
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
Boldt, K., van Reeuwijk, J., Lu, Q., Koutroumpas, K., Nguyen, T.-M. T., Texier, Y., van Beersum, S. E. C., Horn, N., Willer, J. R., Mans, D. A., et al. (2016) · Nature Communications · doi:10.1038/ncomms11491 · Cited by 240 · see citing works
Proteome complexity and the forces that drive proteome imbalance
Harper, J. W., & Bennett, E. J. (2016) · Nature · doi:10.1038/nature19947 · Cited by 234 · see citing works
Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins
Thiébaut, R., Esmiol, S., Lécine, P., Mahfouz, B., Hermant, A., Nicoletti, C., Parnis, S., Perroy, J., Borg, J., Pascoe, L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165420 · Cited by 247 · see citing works
“IKBIP IKBIP interacts with ATG16L1 and with ATG5 two proteins involved in autophagy and CD [4, 69, 71].”
BackgroundAssembling the Community-Scale Discoverable Human Proteome
Wang, M., Wang, J., Carver, J., Pullman, B. S., Cha, S. W., & Bandeira, N. (2018) · Cell Systems · doi:10.1016/j.cels.2018.08.004 · Cited by 201 · see citing works
Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation
Scott, D. C., Rhee, D. Y., Duda, D. M., Kelsall, I. R., Olszewski, J. L., Paulo, J. A., de Jong, A., Ovaa, H., Alpi, A. F., Harper, J. W., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.027 · Cited by 229 · see citing works
“As with WT ARIH1, ARIH1OPEN-OFF associated with many CRL SRs and SEC13-SEC31A yet exhibited a smaller fold change in interactions compared to WT and C357S ARIH1 following 2-hr treatment with MLN4924 (Figures S7B and S7C).”
InfluentialSelf-citationReggiori, F., & Molinari, M. (2022) · Physiological Reviews · doi:10.1152/physrev.00038.2021 · Cited by 222 · see citing works
Computational network biology: Data, models, and applications
Liu, C., Ma, Y., Zhao, J., Nussinov, R., Zhang, Y., Cheng, F., & Zhang, Z. (2019) · Physics Reports · doi:10.1016/j.physrep.2019.12.004 · Cited by 226 · see citing works
Li, Z., Ivanov, A. A., Su, R., González-Pecchi, V., Qi, Q., Liu, S., Webber, P. J., McMillan, E. A., Rusnak, L. E., Pham, C., et al. (2017) · Nature Communications · doi:10.1038/ncomms14356 · Cited by 227 · see citing works
“Newly uncovered MYC binding partners in the OncoPPi network serve as examples to illustrate OncoPPi-inferred new signalling pathways for regulation of MYC-driven cell growth and oncogenic programmes (Figs 2–4).”
InfluentialA Pan-plant Protein Complex Map Reveals Deep Conservation and Novel Assemblies
McWhite, C. D., Papoulas, O., Drew, K., Cox, R. M., June, V. M., Dong, O. X., Kwon, T., Wan, C., Salmi, M. L., Roux, S. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.049 · Cited by 221 · see citing works
eXpression2Kinases (X2K) Web: linking expression signatures to upstream cell signaling networks
Clarke, D. J. B., Kuleshov, M. V., Schilder, B. M., Torre, D., Duffy, M. E., Keenan, A. B., Lachmann, A., Feldmann, A. S., Gundersen, G. W., Silverstein, M. C., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky458 · Cited by 217 · see citing works
“MAP (29) or BioPlex (30) do not Figure 6.”
BackgroundCCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
Bartuzi, P., Billadeau, D. D., Favier, R., Rong, S., Dekker, D., Fedoseienko, A., Fieten, H., Wijers, M., Levels, J. H., Huijkman, N., et al. (2016) · Nature Communications · doi:10.1038/ncomms10961 · Cited by 205 · see citing works
“This line of thought is reinforced by the observation that all 10 members of the COMMD family can engage in the CCC complex 13,41 , and by our recent work showing that the trafficking of Notch, another cargo of this system, is particularly dependent on COMMD9 in various cell lines 14 .”
A genome-wide atlas of co-essential modules assigns function to uncharacterized genes
Wainberg, M., Kamber, R. A., Balsubramani, A., Meyers, R. M., Sinnott-Armstrong, N., Hornburg, D., Jiang, L., Chan, J., Jian, R., Gu, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00840-z · Cited by 204 · see citing works
Mass spectrometry‐based protein–protein interaction networks for the study of human diseases
Richards, A., Eckhardt, M., & Krogan, N. J. (2021) · Molecular Systems Biology · doi:10.15252/msb.20188792 · Cited by 199 · see citing works
“The largest assembly of such PPI networks is the BioPlex database, which has, to date, compiled over 56,533 interactions with 10,961 proteins in HEK293T cells (Huttlin et al, 2015, 2017).”
BackgroundUnderstudied proteins: opportunities and challenges for functional proteomics
Kustatscher, G., Collins, T., Gingras, A., Guo, T., Hermjakob, H., Ideker, T. E., Lilley, K. S., Lundberg, E. K., Marcotte, E. M., Ralser, M., et al. (2022) · Nature Methods · doi:10.1038/s41592-022-01454-x · Cited by 190 · see citing works
Zhou, Y., Liu, Y., Gupta, S., Paramo, M. I., Hou, Y., Mao, C., Luo, Y., Judd, J., Wierbowski, S. D., Bertolotti, M., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01474-0 · Cited by 203 · see citing works
SubCellBarCode: Proteome-wide Mapping of Protein Localization and Relocalization
Orre, L. M., Vesterlund, M., Pan, Y., Arslan, T., Zhu, Y., Fernandez-Woodbridge, A., Frings, O., Fredlund, E., & Lehtiö, J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.11.035 · Cited by 201 · see citing works
A Cellular Mechanism to Detect and Alleviate Reductive Stress.
Manford, A., Rodríguez-Pérez, F., Shih, K. Y., Shi, Z., Berdan, C. A., Choe, M., Titov, D., Nomura, D., & Rapé, M. (2020) · Cell · doi:10.1016/j.cell.2020.08.034 · Cited by 185 · see citing works
“Specific proteins were identified by comparing each IP to a dataset of 40-150 similar (databases for C2C12 and 293T cells) aFLAG IP/mass spectrometry samples using CompPASS analysis (Huttlin et al., 2015).”
MethodComprehensive Overview of Bottom-Up Proteomics Using Mass Spectrometry
Jiang, Y., Balaya, R. D. A., Schuster, D., Neely, B. A., Rosano, G. L., Volkmar, N., Momenzadeh, A., Peters-Clarke, T. M., Egbert, S., Kreimer, S. D., et al. (2024) · ACS Measurement Science Au · doi:10.1021/acsmeasuresciau.3c00068 · Cited by 200 · see citing works
Drew, K., Lee, C., Huizar, R. L., Tu, F., Borgeson, B., McWhite, C. D., Ma, Y., Wallingford, J. B., & Marcotte, E. M. (2017) · Molecular Systems Biology · doi:10.15252/msb.20167490 · Cited by 191 · see citing works
“…protein interaction mapping efforts in particular have greatly expanded the set of known human protein interactions, namely BioPlex (Huttlin et al, 2015), Hein et al (Hein et al, 2015), and Wan et al (Wan et al, 2015), collectively comprising 9,063 mass spectrometry shotgun…”
BackgroundMethodInfluentialExploring genetic suppression interactions on a global scale
van Leeuwen, J. S., Pons, C., Mellor, J. C., Yamaguchi, T. N., Friesen, H., Koschwanez, J. H., Ušaj, M. M., Pechlaner, M., Takar, M., Ušaj, M., et al. (2016) · Science · doi:10.1126/science.aag0839 · Cited by 176 · see citing works
Network Medicine in the Age of Biomedical Big Data
Sonawane, A. R., Weiss, S. T., Glass, K., & Sharma, A. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00294 · Cited by 189 · see citing works
“-throughput mapping of the interactome has provided a molecular interaction map of the genes encoding proteins that might drive an underlying pathophenotype (Barabasi et al., 2011; Hein et al., 2015; Huttlin et al., 2015; Kamburov et al., 2009; Rolland et al., 2014; Zhang et al., 2013). Understanding disease associate…”
BackgroundMethodZhou, Y., Hou, Y., Shen, J., Mehra, R., Kallianpur, A., Culver, D. A., Gack, M. U., Farha, S., Zein, J., Comhair, S., et al. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000970 · Cited by 180 · see citing works
Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases
Yang, D., Wang, X., Zhang, L., Fang, Y., Zheng, Q., Liu, X., Yu, W., Chen, S., Ying, J., & Hua, F. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00828-0 · Cited by 179 · see citing works
“Mutations in the human VAMP-associated protein B (hVAPB)-induced neurotoxicity pathway regulators were mainly enriched for proteins related to LD dynamics [127] and controlled the degradation of misfolded proteins via binding TTC39B [128].”
BackgroundCory, S. A., Vranken, J. G. V., Brignole, E. J., Patra, S., Winge, D. R., Drennan, C. L., Rutter, J. P., & Barondeau, D. P. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1702849114 · Cited by 178 · see citing works
“Recent affinity capture MS studies further support this hypothesis by providing evidence that ACP interacts with at least 7 of the 11 human LYR proteins (67, 68), including LYR proteins that also interact with HSC20 and are implicated in the Fe–S cluster delivery mechanism (10, 69).”
BackgroundULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
Wang, B., Maxwell, B. A., Joo, J. H., Gwon, Y., Messing, J., Mishra, A., Shaw, T. I., Ward, A. L., Quan, H., Sakurada, S. M., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.03.027 · Cited by 174 · see citing works
Methods for Physical Characterization of Phase-Separated Bodies and Membrane-less Organelles
Mitrea, D. M., Chandra, B., Ferrolino, M. C., Gibbs, E. B., Tolbert, M., White, M. R., & Kriwacki, R. W. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.07.006 · Cited by 173 · see citing works
Protein interaction landscapes revealed by advanced in vivo cross-linking–mass spectrometry
Wheat, A. J., Yu, C., Wang, X., Burke, A. M., Chemmama, I. E., Kaake, R. M., Baker, P. R., Rychnovsky, S. D., Yang, J. H., & Huang, L. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2023360118 · Cited by 172 · see citing works
Vranken, J. G. V., Jeong, M.-Y., Wei, P., Chen, Y.-C., Gygi, S. P., Winge, D. R., & Rutter, J. P. (2016) · eLife · doi:10.7554/elife.17828 · Cited by 171 · see citing works
“These results are further supported by proteomics-based interaction studies, which identify human ACP, NFS1, and ISD11 as mutually interacting proteins in mammalian cells (Huttlin et al., 2015).”
ResultSONAR Discovers RNA-Binding Proteins from Analysis of Large-Scale Protein-Protein Interactomes
Brannan, K. W., Jin, W., Huelga, S. C., Banks, C. A. S., Gilmore, J. M., Florens, L. A., Washburn, M. P., Nostrand, E. L. V., Pratt, G. A., Schwinn, M. K., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.09.003 · Cited by 170 · see citing works
“Next, we generated ‘‘neighborhoods’’ for all proteins in the human BioPlex PPI data set, which consists of dozens of thousands of interactions (Huttlin et al., 2015).”
Piecing Together the Patchwork of Contact Sites
Gatta, A. T., & Levine, T. P. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.08.010 · Cited by 167 · see citing works
Recent progress in mass spectrometry proteomics for biomedical research
Li, X., Wang, W., & Chen, J. (2017) · Science China Life Sciences · doi:10.1007/s11427-017-9175-2 · Cited by 166 · see citing works
Target 2035: probing the human proteome
Carter, A. J., Kraemer, O., Zwick, M., Mueller‐Fahrnow, A., Arrowsmith, C. H., & Edwards, A. M. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.06.020 · Cited by 169 · see citing works
Occupancy maps of 208 chromatin-associated proteins in one human cell type
Partridge, E. C., Chhetri, S. B., Prokop, J. W., Ramaker, R. C., Jansen, C. S., Goh, S.-T., Mackiewicz, M., Newberry, K. M., Brandsmeier, L. A., Meadows, S. K., et al. (2020) · Nature · doi:10.1038/s41586-020-2023-4 · Cited by 154 · see citing works
“Of the GATAD2A-associated CAPs, ZNF219 38 , SMAD4 39 , and RARA 40 have previously been associated with the NuRD complex (Fig.”
Characterizing Protein–Protein Interactions Using Mass Spectrometry: Challenges and Opportunities
Smits, A. H., & Vermeulen, M. (2016) · Trends in biotechnology · doi:10.1016/j.tibtech.2016.02.014 · Cited by 162 · see citing works
“MS-based PPI identification has become instrumental in biologically focused investigations for a single or a few proteins of interest and also in large-scale studies [5–7].”
BackgroundUBE2O remodels the proteome during terminal erythroid differentiation
Nguyen, A. T., Prado, M. A., Schmidt, P. J., Sendamarai, A. K., Wilson‐Grady, J., Min, M., Campagna, D. R., Tian, G., Shi, Y., Dederer, V., et al. (2017) · Science · doi:10.1126/science.aan0218 · Cited by 164 · see citing works
“p-value) Protein processing in endoplasmic reticulum Protein export Endocytosis Ribosome (14) (12) (9) (4)”
BackgroundInfluentialJohnson, B., Leek, A. N., Solé, L., Maverick, E. E., Levine, T. P., & Tamkun, M. M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805757115 · Cited by 166 · see citing works
“1-modifying kinases (CDK5, p38 MAPK, src) (51–53) and phosphatases (calcineurin) (3, 40) have not been confirmed to be part of the VAP interactome (19).”
BackgroundFAM134B oligomerization drives endoplasmic reticulum membrane scission for ER‐phagy
Jiang, X. M., Wang, X., Ding, X., Du, M., Li, B., Weng, X., Zhang, J., Li, L., Tian, R. L., Zhu, Q., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019102608 · Cited by 162 · see citing works
“Another ER-phagy receptor, SEC62, also locates on ER sheets (Fumagalli et al , 2016), and interestingly, SEC62 associates with FAM134C (Huttlin et al , 2015), a FAM134 family member that has broader tissue distribution than FAM134B (Kurth et al , 2009).”
Liu, F., Lössl, P., Rabbitts, B. M., Balaban, R. S., & Heck, A. J. R. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000470 · Cited by 164 · see citing works
“Nevertheless, it is noteworthy that similar to BioID/APEX, XL-MS experiments merely reveal protein pairs that are spatially close, which does not necessarily imply a functionally relevant interaction.”
InfluentialEndosomal Retrieval of Cargo: Retromer Is Not Alone
McNally, K. E., & Cullen, P. J. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.06.005 · Cited by 164 · see citing works
SETD2: an epigenetic modifier with tumor suppressor functionality
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Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability
Anikster, Y., Haack, T. B., Vilboux, T., Pode‐Shakked, B., Thöny, B., Shen, N., Guarani, V., Meißner, T., Mayatepek, E., Trefz, F. K., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.01.002 · Cited by 162 · see citing works
“The spectra were searched using Sequest as previously described.(7) CompPASS analysis was applied to distinguish high-confidence protein in-”
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Discovery and significance of protein-protein interactions in health and disease
Greenblatt, J. F., Alberts, B., & Krogan, N. J. (2024) · Cell · doi:10.1016/j.cell.2024.10.038 · Cited by 171 · see citing works
Understanding extracellular vesicle diversity – current status
Greening, D. W., & Simpson, R. J. (2018) · Expert Review of Proteomics · doi:10.1080/14789450.2018.1537788 · Cited by 160 · see citing works
“Proteomicbased protein–protein interaction identification has become instrumental in biologically focused investigations for single or targeted proteins of interest [315].”
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“016 [58]; binary PPIs discovered by high-throughput yeast two-hybrid systems in three datasets [33, 59, 60]; signaling networks revealed by low-throughput experiments from SignaLink2.”
BackgroundAPID database: redefining protein–protein interaction experimental evidences and binary interactomes
Alonso-López, D., Campos-Laborie, F., Gutiérrez, M. A., Lambourne, L., Calderwood, M., Vidal, M., & Rivas, J. D. L. (2019) · Database J. Biol. Databases Curation · doi:10.1093/database/baz005 · Cited by 152 · see citing works
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VDAC1 functions in Ca2+ homeostasis and cell life and death in health and disease
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- 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 · 2013: 1
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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