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Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ

原位 生物 蛋白质组 计算生物学 细胞生物学 进化生物学 遗传学 物理 气象学
作者
Valentina Cappelletti,Thomas Häuser,Ilaria Piazza,Monika Pepelnjak,Liliana Malinovska,Tobias Fuhrer,Yaozong Li,Christian Dörig,Paul J. Boersema,Ludovic Gillet,Jan Großbach,Aurélien Dugourd,Julio Sáez-Rodríguez,Andreas Beyer,Nicola Zamboni,Amedeo Caflisch,Natalie de Souza,Paola Picotti
出处
期刊:Cell [Elsevier]
卷期号:184 (2): 545-559.e22 被引量:116
标识
DOI:10.1016/j.cell.2020.12.021
摘要

•Dynamic structural proteomic screens detect functional changes at high resolution•Detect enzyme activity, phosphorylation, and molecular interactions in situ•Generate new molecular hypotheses and increase functional proteomics coverage•Enabled discovery of a regulatory mechanism of glucose uptake in E. coli Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites. Comparison with prior knowledge, including other 'omics data, showed that LiP-MS detects many known functional alterations within well-studied pathways. It suggested distinct metabolite-protein interactions and enabled identification of a fructose-1,6-bisphosphate-based regulatory mechanism of glucose uptake in E. coli. The structural readout dramatically increases classical proteomics coverage, generates mechanistic hypotheses, and paves the way for in situ structural systems biology. Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites. Comparison with prior knowledge, including other 'omics data, showed that LiP-MS detects many known functional alterations within well-studied pathways. It suggested distinct metabolite-protein interactions and enabled identification of a fructose-1,6-bisphosphate-based regulatory mechanism of glucose uptake in E. coli. The structural readout dramatically increases classical proteomics coverage, generates mechanistic hypotheses, and paves the way for in situ structural systems biology.
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