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Quantitative dissection and modeling of the NF-κB p100-p105 module reveals interdependent precursor proteolysis

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Item Type:Article
Title:Quantitative dissection and modeling of the NF-κB p100-p105 module reveals interdependent precursor proteolysis
Creators Name:Yilmaz, Z.B. and Kofahl, B. and Beaudette, P. and Baum, K. and Ipenberg, I. and Weih, F. and Wolf, J. and Dittmar, G. and Scheidereit, C.
Abstract:The mechanisms that govern proteolytic maturation or complete destruction of the precursor proteins p100 and p105 are fundamental to homeostasis and activation of NF-{kappa}B; however, they remain poorly understood. Using mass-spectrometry-based quantitative analysis of noncanonical LT{beta}R-induced signaling, we demonstrate that stimulation induces simultaneous processing of both p100 and p105. The precursors not only form hetero-oligomers but also interact with the ATPase VCP/p97, and their induced proteolysis strictly depends on the signal response domain (SRD) of p100, suggesting that the SRD-targeting proteolytic machinery acts in cis and in trans. Separation of cellular pools by isotope labeling revealed synchronous dynamics of p105 and p100 proteolysis. The generation of p50 and p52 from their precursors depends on functional VCP/p97. We have developed quantitative mathematical models that describe the dynamics of the system and predict that p100-p105 complexes are signal responsive.
Keywords:Adenosine Triphosphatases, Biological Models, Cell Cycle Proteins, HEK293 Cells, HeLa Cells, Kinetics, Lymphotoxin {beta} Receptor, NF-{kappa} B p50 Subunit, NF-{kappa} B p52 Subunit, Phosphorylation, Post-Translational Protein Processing, Protein Precursors, Proteolysis, Animals, Mice
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press (U.S.A.)
Volume:9
Number:5
Page Range:1756-1769
Date:11 December 2014
Official Publication:https://doi.org/10.1016/j.celrep.2014.11.014
PubMed:View item in PubMed

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