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Title

A systems wide mass spectrometric based linear motif screen to identify dominant in-vivo interacting proteins for the ubiquitin ligase MDM2

Authors
Nicholson, Judith
Way, Luke
A. Blackburn, Elizabeth
D. Walkinshaw, Malcolm
L. Ball, Kathryn
R. Hupp, Ted
Published in Cellular Signalling. 2014, vol. 26, no. 6, p. 1243-1257
Abstract Linear motifs mediate protein–protein interactions (PPI) that allow expansion of a target protein interactome at a systems level. This study uses a proteomics approach and linear motif sub-stratifications to expand on PPIs of MDM2. MDM2 is a multi-functional protein with over one hundred known binding partners not stratified by hierarchy or function. A new linear motif based on a MDM2 interaction consensus is used to select novel MDM2 interactors based on Nutlin-3 responsiveness in a cell-based proteomics screen. MDM2 binds a subset of peptide motifs corresponding to real proteins with a range of allosteric responses to MDM2 ligands. We validate cyclophilin B as a novel protein with a consensus MDM2 binding motif that is stabilised by Nutlin-3 in vivo, thus identifying one of the few known interactors of MDM2 that is stabilised by Nutlin-3. These data invoke two modes of peptide binding at the MDM2 N-terminus that rely on a consensus core motif to control the equilibrium between MDM2 binding proteins. This approach stratifies MDM2 interacting proteins based on the linear motif feature and provides a new biomarker assay to define clinically relevant Nutlin-3 responsive MDM2 interactors.
Identifiers
PMID: 24583282
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Research group Chimie et protéomique clinique (270)
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NICHOLSON, Judith et al. A systems wide mass spectrometric based linear motif screen to identify dominant in-vivo interacting proteins for the ubiquitin ligase MDM2. In: Cellular Signalling, 2014, vol. 26, n° 6, p. 1243-1257. https://archive-ouverte.unige.ch/unige:38237

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Deposited on : 2014-06-26

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