A multi-scale map of cell structure fusing protein images and interactions
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Abstract
ABSTRACT The eukaryotic cell is a multi-scale structure with modular organization across at least four orders of magnitude 1,2 . Two central approaches for mapping this structure – protein fluorescent imaging and protein biophysical association – each generate extensive datasets but of distinct qualities and resolutions that are typically treated separately 3,4 . Here, we integrate immunofluorescent images in the Human Protein Atlas 5 with ongoing affinity purification experiments from the BioPlex resource 6 to create a unified hierarchical map of eukaryotic cell architecture. Integration involves configuring each approach to produce a general measure of protein distance, then calibrating the two measures using machine learning. The evolving map, called the Multi-Scale Integrated Cell (MuSIC 1.0), currently resolves 69 subcellular systems of which approximately half are undocumented. Based on these findings we perform 134 additional affinity purifications, validating close subunit associations for the majority of systems. The map elucidates roles for poorly characterized proteins, such as the appearance of FAM120C in chromatin; identifies new protein assemblies in ribosomal biogenesis, RNA splicing, nuclear speckles, and ion transport; and reveals crosstalk between cytoplasmic and mitochondrial ribosomal proteins. By integration across scales, MuSIC substantially increases the mapping resolution obtained from imaging while giving protein interactions a spatial dimension, paving the way to incorporate many molecular data types in proteome-wide maps of cells.
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Other systematic image-based approaches have catalogued the location of human proteins in several cell types and used the locations of proteins and structures within cells to identify differences in intracellular spatial patterns among cells in distinct states.
“Other systematic image-based approaches have catalogued the location of human proteins in several cell types and used the locations of proteins and structures within cells to identify differences in intracellular spatial patterns among cells in distinct states6–12,19,29.”
From Integrated intracellular organization and its variations in human iPS cells (2023) · cites this paper as [11]
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- Authors
- Qin, Y., Huttlin, E. L., Winsnes, C. F., Gosztyla, M. L., Wacheul, L., Kelly, M. R., Blue, S. M., Zheng, F., Chen, M., Schaffer, L. V., Licon, K., Bäckström, A., Vaites, L. P., Lee, J. J., Ouyang, W., Liu, S. N., Zhang, T., Silva, E., Park, J., Pitea, A., Kreisberg, J. F., Gygi, S. P., Ma, J., Harper, J. W., Yeo, G. W., Lafontaine, D. L. J., Lundberg, E., & Ideker, T.
- Affiliations
- University of California San Diego (US)
- Harvard University (US)
- Science for Life Laboratory (SE)
- Université Libre de Bruxelles (BE)
- Peking University (CN)
- Corresponding author
- Lundberg, Emma
- Ideker, Trey
- ORCID
- Qin, Yue
- Huttlin, Edward L.
- Winsnes, Casper F.
- Gosztyla, Maya L.
- Wacheul, Ludivine
- Kelly, Marcus R.
- Blue, Steven M.
- Zheng, Fan
- Chen, Michael
- Schaffer, Leah V.
- Bäckström, Anna
- Lee, John J.
- Ouyang, Wei
- Liu, Sophie N.
- Zhang, Tian
- Silva, Erica
- Park, Jisoo
- Pitea, Adriana
- Kreisberg, Jason F.
- Gygi, Steven P.
- Ma, Jianzhu
- Harper, J. Wade
- Yeo, Gene W.
- Lafontaine, Denis L. J.
- Lundberg, Emma
- Ideker, Trey
- Venue
- Nature
- Published
- 2021-11-24
- Volume
- 600
- Issue
- 7889
- Pages
- 536-542
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9053732
- OpenAlex
- W3215994910
- Cited by
- 82
- References
- 36
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 20 · 2023: 22 · 2022: 17 · 2021: 3
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- www.springer.com/tdm (tdm)
- www.springer.com/tdm (vor)
- Locations
- Nature (publishedVersion, public-domain)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Familjen Erling-Perssons Stiftelse (2017-05327)
- Fonds De La Recherche Scientifique - FNRS
- Knut och Alice Wallenbergs Stiftelse (2016-0204)
- Vetenskapsrådet (2017-05327)
- Science for Life Laboratory
- National Institutes of Health (CA209891, HG009889, GM 103504, HG004659)
- National Heart, Lung, and Blood Institute (R01HL137223)
- National Institute of Mental Health (U01MH115747)
- National Human Genome Research Institute (R01HG009979, R01HG004659, U24HG006673, U41HG009889)
- National Cancer Institute (U54CA209891, F99CA264422, R50CA243885, T32CA067754)
- National Institute of General Medical Sciences (P41GM103504)
- 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
- cellular architecture, subcellular organization, protein-protein interaction, immunofluorescence microscopy, affinity purification, multiscale integration, Human Protein Atlas, BioPlex, rRNA maturation, RPS3A, splicing, chromatin, machine learning calibration
- MeSH terms
- Chromatin, Chromosomes, Humans, RNA, Ribosomal, RNA-Binding Proteins, Proteome, Nuclear Matrix-Associated Proteins, Antigens, Nuclear
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