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Towards an in silico cell


The cell is a multi-scale structure with modular organization across at least four orders of magnitude. 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. Here, we integrate immunofluorescence images in the Human Protein Atlas with affinity purification experiments from the BioPlex resource to create a unified hierarchical map of eukaryotic cell architecture. Integration is achieved by configuring each approach to produce a general measure of protein distance, then calibrating the two measures using machine learning. The 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 reveals ribosome biogenesis components, including a novel pre-ribosomal RNA processing assembly and numerous accessory factors which we show govern rRNA maturation. The map also elucidates roles for SRRM1 and FAM120C in chromatin and for RPS3A in splicing. 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 diverse types of molecular data to create proteome-wide cell maps.

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