PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex.

Keap1 is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. Inhibition of Keap1-dependent ubiquitination of the bZIP transcription factor Nrf2 enables Nrf2 to activate a cyto-protective transcriptional program that counters the damaging effects of oxidative ...
stress. In this report we have identified a member of the phosphoglycerate mutase family, PGAM5, as a novel substrate for Keap1. The N terminus of the PGAM5 protein contains a conserved NXESGE motif that binds to the substrate binding pocket in the Kelch domain of Keap1, whereas the C-terminal PGAM domain binds Bcl-X(L). Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Quinone-induced oxidative stress and the chemopreventive agent sulforaphane inhibit Keap1-dependent ubiquitination of PGAM5. The identification of PGAM5 as a novel substrate of Keap1 suggests that Keap1 regulates both transcriptional and post-transcriptional responses of mammalian cells to oxidative stress.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, COS Cells, Cell Cycle Proteins, Cell Line, Cercopithecus aethiops, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Oxidation-Reduction, Phylogeny, Recombinant Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Transfection, Ubiquitin-Protein Ligases, bcl-X Protein
J. Biol. Chem.
Date: Dec. 08, 2006
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