Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling
| Autor: | Anne-Claude Gingras, Cecilia Blikstad, Katharine S. Ullman, Jagoree Roy, Vikash K Yadav, Izabella Krystkowiak, Malika Amyn Kaderali, Jennifer T. Wang, Douglas R. Mackay, Ylva Ivarsson, Devin A. Bradburn, Eirini Tsekitsidou, Callie P. Wigington, Cassandra J. Wong, Tim Stearns, Su Hyun Hong, Nikhil P Damle, Martha S. Cyert, Eduard Resch, Shou-Ling Xu, Norman E. Davey |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Saccharomyces cerevisiae Proteins
Proteome In silico Phosphatase Amino Acid Motifs Active Transport Cell Nucleus Saccharomyces cerevisiae Computational biology Biology Mass Spectrometry Article 03 medical and health sciences 0302 clinical medicine Humans Degeneracy (biology) Biotinylation Computer Simulation Short linear motif Protein Interaction Maps Phosphorylation Receptor Notch1 Nuclear pore Molecular Biology Calcineurin phosphatase Binding affinities 030304 developmental biology Centrosome 0303 health sciences Chemistry Calcineurin HEK 293 cells Cell Biology Phosphoric Monoester Hydrolases Nuclear Pore Complex Proteins HEK293 Cells Nuclear transport Signal transduction 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | Mol Cell |
| Popis: | SummaryShort linear motifs (SLiMs) drive dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN)/PP2B, the Ca2+-activated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in vivo SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including NOTCH1, which we establish as a CN substrate. Unexpectedly, CN shows SLiM-dependent proximity to centrosomal and nuclear pore complex (NPC) proteins – structures where Ca2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear transport reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca2+ and CN signaling and demonstrates synergy between experimental and computational methods, establishing a blueprint for examining SLiM-based networks. |
| Databáze: | OpenAIRE |
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