Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling.

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

SUBMITTER: Wigington CP 

PROVIDER: S-EPMC7416808 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature