Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling.

Journal article


Yadav, V. 2020. Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling. Molecular cell. Vol 79 (Issue 2), pp. 342-358. https://doi.org/10.1016/j.molcel.2020.06.029
AuthorsYadav, V.
Abstract

Short 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.

KeywordsShort Linear Motifs; Calcineurin; In vivo; Proteins
Year2020
JournalMolecular cell
Journal citationVol 79 (Issue 2), pp. 342-358
PublisherElseiver
ISSN1097-2765
1097-4164
Digital Object Identifier (DOI)https://doi.org/10.1016/j.molcel.2020.06.029
Web address (URL)https://doi.org/10.1016/j.molcel.2020.06.029
Output statusPublished
Publication dates
Online08 Jul 2020
Online16 Jul 2020
Publication process dates
Accepted26 May 2020
Deposited15 Jun 2023
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