Multimodal cell maps as a foundation for structural and functional genomics

• 成果类型: Article
• 署名作者: Schaffer, Leah V.; Hu, Mengzhou; Qian, Gege; Moon, Kyung-Mee; Pal, Abantika; Soni, Neelesh; Latham, Andrew P.; Vaites, Laura Pontano; Tsai, Dorothy; Mattson, Nicole M.; Licon, Katherine; Bachelder, Robin; Cesnik, Anthony; Gaur, Ishan; Le, Trang; Leineweber, William; Palar, Aji; Pulido, Ernst; Qin, Yue; Zhao, Xiaoyu; Churas, Christopher; Lenkiewicz, Joanna; Chen, Jing; Ono, Keiichiro; Pratt, Dexter; Zage, Peter; Echeverria, Ignacia; Sali, Andrej; Harper, J. Wade; Gygi, Steven P.; Foster, Leonard J.; Huttlin, Edward L.; Lundberg, Emma; Ideker, Trey
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of British Columbia; University of California System; University of California San Francisco; Harvard University; Harvard Medical School; Stanford University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of California System; University of California San Diego; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Stanford University; Royal Institute of Technology; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Diego; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-0984
• DOI: 10.1038/s41586-025-08878-3
• 发表日期: 2025-06-05
• 关键词: protein-protein interactions; cancer driver genes; high-throughput; localization; architecture; expression; complexes; networks; atlas

摘要

Human cells consist of a complex hierarchy of components, many of which remain unexplored1,2. 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 10-8 to 10-5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models3. 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 genomes4, 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.