Multimodal cell maps as a foundation for structural and functional genomics
Human cells consist of a complex hierarchy of components, many of which remain unexplored<sup>1,2</sup>. Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10<sup>-8</sup> to 10<sup>-5</sup> m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models<sup>3</sup>. We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag-Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes<sup>4</sup>, identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.
Authors
- Abantika Pal (ORCID: https://orcid.org/0000-0002-9224-9801)
- Christopher Churas (ORCID: https://orcid.org/0000-0001-9998-705X)
- Neelesh Soni (ORCID: https://orcid.org/0000-0002-9333-7491)
- Anthony J. Cesnik (ORCID: https://orcid.org/0000-0002-5326-7134)
- Laura Pontano Vaites
- Joanna Lenkiewicz (ORCID: https://orcid.org/0000-0001-7252-8638)
- Andrej Săli (ORCID: https://orcid.org/0000-0003-0435-6197)
- William D. Leineweber (ORCID: https://orcid.org/0000-0003-3069-398X)
- Leah V. Schaffer (ORCID: https://orcid.org/0000-0001-6339-9141)
- Dexter Pratt (ORCID: https://orcid.org/0000-0002-1471-9513)
- Nicole M. Mattson (ORCID: https://orcid.org/0000-0001-5881-3387)
- Leonard J. Foster (ORCID: https://orcid.org/0000-0001-8551-4817)
- J. Wade Harper (ORCID: https://orcid.org/0000-0002-6944-7236)
- Emma K. Lundberg (ORCID: https://orcid.org/0000-0001-7034-0850)
- Keiichiro Ono (ORCID: https://orcid.org/0000-0003-4042-3748)
- Edward L. Huttlin (ORCID: https://orcid.org/0000-0002-1822-1173)
- Ernst H. Pulido (ORCID: https://orcid.org/0000-0002-3616-9743)
- Xiaoyu Zhao (ORCID: https://orcid.org/0000-0002-6081-2196)
- Gege Qian (ORCID: https://orcid.org/0000-0001-5068-0399)
- Trang T. Le (ORCID: https://orcid.org/0000-0003-3737-6565)
- Peter E. Zage (ORCID: https://orcid.org/0000-0003-1837-2315)
- Katherine Licon
- Mengzhou Hu (ORCID: https://orcid.org/0000-0002-1571-8029)
- Ignacia Echeverria (ORCID: https://orcid.org/0000-0003-4717-1467)
- Steven P. Gygi (ORCID: https://orcid.org/0000-0001-7626-0034)
- Ishan Gaur
- Robin E. Bachelder (ORCID: https://orcid.org/0000-0001-7502-2907)
- Kyung‐Mee Moon (ORCID: https://orcid.org/0000-0003-3796-720X)
- Andrew P. Latham (ORCID: https://orcid.org/0000-0002-9338-7253)
- Trey Ideker (ORCID: https://orcid.org/0000-0002-1708-8454)
- Jing Chen (ORCID: https://orcid.org/0000-0001-7974-3090)
- Yue Qin (ORCID: https://orcid.org/0000-0002-0496-7134)
- Aji Palar (ORCID: https://orcid.org/0000-0001-9357-6970)
- D. S. Tsai (ORCID: https://orcid.org/0000-0002-1484-7961)
Institutions
- Broad Institute (US)
- Harvard University (US)
- University of British Columbia (CA)
- Palo Alto University (US)
- University of California, San Francisco (US)
- University of California San Diego (US)
- Quantitative BioSciences (US)
- Chan Zuckerberg Initiative (United States) (US)
- Canada's Michael Smith Genome Sciences Centre (CA)
- La Jolla Bioengineering Institute (US)
- KTH Royal Institute of Technology (SE)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1038/s41586-025-08878-3
- Citations
- 22
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 16.12