Multimodal cell maps as a foundation for structural and functional genomics
Abstract
Abstract 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.
Article Details
Authors (34)
Leah V. Schaffer
Mengzhou Hu
Gege Qian
Kyung-Mee Moon
Abantika Pal
Neelesh Soni
Andrew P. Latham
Laura Pontano Vaites
Dorothy Tsai
Nicole M. Mattson
Katherine Licon
Robin Bachelder
Anthony Cesnik
Ishan Gaur
Trang Le
William Leineweber
Aji Palar
Ernst Pulido
Yue Qin
Xiaoyu Zhao
Christopher Churas
Joanna Lenkiewicz
Jing Chen
Keiichiro Ono
Dexter Pratt
Peter Zage
Ignacia Echeverria
Andrej Sali
J. Wade Harper
Steven P. Gygi
Leonard J. Foster
Edward L. Huttlin
Emma Lundberg
Trey Ideker