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A comprehensive motifs-based interactome of the C/EBPα transcription factor

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Title:A comprehensive motifs-based interactome of the C/EBPα transcription factor
Creators Name:Ramberger, E. and Sapozhnikova, V. and Kowenz-Leutz, E. and Zimmermann, K. and Nicot, N. and Nazarov, P.V. and Perez-Hernandez, D. and Reimer, U. and Mertins, P. and Dittmar, G. and Leutz, A.
Abstract:The pioneering transcription factor C/EBPα coordinates cell fate and cell differentiation. C/EBPα represents an intrinsically disordered protein with multiple short linear motifs and extensive post-translational side chain modifications (PTM), reflecting its modularity and functional plasticity. Here, we combined arrayed peptide matrix screening (PRISMA) with biotin ligase proximity labeling proteomics (BioID) to generate a linear, isoform specific and PTM-dependent protein interaction map of C/EBPα in myeloid cells. The C/EBPα interactome comprises promiscuous and PTM-regulated interactions with protein machineries involved in gene expression, epigenetics, genome organization, DNA replication, RNA processing, and nuclear transport as the basis of functional C/EBPα plasticity. Protein interaction hotspots were identified that coincide with homologous conserved regions of the C/EBP family and revealed interaction motifs that score as molecular recognition features (MoRF). PTMs alter the interaction spectrum of multi-valent C/EBP-motifs to configure a multimodal transcription factor hub that allows interaction with multiple co-regulatory components, including BAF/SWI-SNF or Mediator complexes. Combining PRISMA and BioID acts as a powerful strategy to systematically explore the interactomes of intrinsically disordered proteins and their PTM-regulated, multimodal capacity.
Keywords:Intrinsic Disorder, CEBPA Interactome, BioID, Peptide Array, Mass Spectrometry
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.12.28.424569
Date:28 December 2020
Official Publication:https://doi.org/10.1101/2020.12.28.424569

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